Articles de revues : « Gut microbiota, vitiligo, melanoma »

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Mohamed, Asmaa, Jennifer Vella, Mary Jo Turk et Yina H. Huang. « Dendritic cells instruct differentiation of tissue resident memory T cells in the skin to promote durable tumor immunity ». Journal of Immunology 208, n^o 1_Supplement (1 mai 2022) : 57.14. http://dx.doi.org/10.4049/jimmunol.208.supp.57.14.

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Abstract A subset of melanoma patients treated with immune checkpoint inhibitors develops vitiligo, a CD8 T cell-mediated autoimmune disease associated with improved patient survival. Using a melanoma-associated vitiligo (MAV) mouse model, CD8 tissue resident memory (TRM) T cells in vitiligo skin were found to be necessary and sufficient for durable tumor immunity. Using immunofluorescence microscopy, we found that skin TRM cells formed large aggregates with CD11c myeloid cells proximal to hair follicles. CD11c depletion resulted in TRM cell loss, revealing an unexpected requirement for continued T cell-dendritic cell (DC) interactions in TRM cell maintenance. We hypothesize that DCs provide instructive signals that are required for continued in situ maturation of CD8 TRM cells. To identify these signals, we disrupted Toll Like Receptor (TLR) signaling in DCs by ablating the MyD88 adapter protein and observed a reduction in skin TRM cell accumulation. This prompted us to explore a role for the microbiota in CD8 TRM formation. Treatment with broad spectrum antibiotics resulted in a 50% reduction in vitiligo incidence. B6 mice from vendors with microbiota differences, exhibited divergent MAV incidence, but upon cohousing or fecal transplantation, mice from both sources exhibited high MAV incidence. Collectively, these findings indicates that the gut-skin microbiota axis plays a critical role in generating tumor protective TRM cells. Future studies seek to identify microbial antigens responsible for promoting TRM differentiation. Supported by T32-AI007363 P30-CA023108

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Akhtar, S., E. Dellacecca, V. Engelhard, K. Knight et C. Le Poole. « 828 Dysbiosis of gut microbiota by ampicillin exacerbates vitiligo ». Journal of Investigative Dermatology 137, n^o 5 (mai 2017) : S142. http://dx.doi.org/10.1016/j.jid.2017.02.853.

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Vujkovic-Cvijin, Ivan, Maria Wei, Nicholas P. Restifo et Yasmine Belkaid. « Role for skin-associated microbiota in development of endogenous anti-melanocyte immunity in vitiligo ». Journal of Immunology 198, n^o 1_Supplement (1 mai 2017) : 58.14. http://dx.doi.org/10.4049/jimmunol.198.supp.58.14.

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Abstract Despite major advances in immunotherapeutic approaches designed to bolster endogenous immune responses against tumors, metastatic melanoma remains associated with high mortality and rapid progression. Development of novel approaches toward enhancing endogenous immune responses against melanoma constitutes a critical step toward the management of disease. Of note, initiating immune responses against non-mutated melanocyte-specific protein antigens has shown efficacy in augmenting immunotherapies. Vitiligo is an autoimmune disease characterized by immune-mediated destruction of melanocytes, though the etiology of this disease remains poorly understood. Microbes have been recently found to have a profound effect on immune processes of the skin, including those that are associated with vitiligo progression. Identifying skin-resident microbes that initiate or exacerbate anti-melanocyte immunity, as well as the precise pathways that mediate these processes, may provide a novel framework for the development of immunotherapies to augment anti-tumor immune responses and efficacy of existing therapies. Thus, we have recruited a cohort of individuals with vitiligo and profiled their skin microbiomes at various body sites. We have found that vitiligo subjects harbor a skin microbiota that is unique from healthy subjects, and have isolated numerous vitiligo-associated bacteria. Furthermore, we have adapted a mouse model of vitiligo to understand mechanisms of host-microbiome interactions in this setting. Interrogation of this host-microbiome relationship may lead to the identification of novel targets and pathways by which to treat vitiligo and augment melanoma immunotherapies.

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Frankel, Arthur E., Kenya Honda, Bruce Roberts, Rose Szabady, Amit Reddy, Johnny Lightcap, Steve McClellan, Sachin Kumar Deshmukh et Andrew Y. Koh. « Precision probiotic therapy enhances immune checkpoint therapy efficacy in melanoma bearing mice. » Journal of Clinical Oncology 37, n^o 15_suppl (20 mai 2019) : e14195-e14195. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14195.

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e14195 Background: Immune checkpoint inhibitor therapy, ICT, achieves remissions in melanoma patients but factors modulating response are not well defined. Our group (Frankel et al. Neoplasia 2017) and others have identified specific gut microbiota associated with improved ICT response. Recently, we identified specific gut microbiota that induce adaptive immune responses and potentiate ICT (Tanoue et al. Nature 2019). In this study, we determined whether this predefined consortia of gut microbiota augment ICT efficacy in melanoma bearing mice. Methods: Mice (C57BL/6, 6-8wk old, female, Jackson, n = 4-12 mice) received ± antibiotic water (penicillin G 1500U/mL + streptomycin 2mg/mL) for 6 d to deplete gut microbiota. Mice were then inoculated with 105 B16F10 melanoma cells SQ. At d 4, 8, 12 post-tumor inoculation, 0.2 mg anti-mCTLA4 + anti-mPD1 antibodies (Bio X Cell) were administered IP. Precision probiotic therapies included Vedanta Bioscience VE800 (Tanoue et al., Nature 2019), VE804 (same as VE800 without R. lactatiformans and F. ulcerans), VE411 (four Clostridial firmicutes) (Narushima, 2014), and Lactobacillus acidophilus (ATCC 4356) probiotics were given via gavage (1x109 cfu) starting day +1 after tumor inoculation and 3xwkly. Loss of survival was defined as death or tumor diameters ≥ 2 cm. Tumor growth inhibition, TGI = (1- mean treated tumor volume/mean control tumor volume) x 100%. Tumor mononuclear cells were isolated for flow cytometry for murine CD4, CD8, and CD11c. Results: TGI in mice with intact gut microbiota and treated with ICT was 84 ± 4% (SEM). Pre-treatment antibiotics reduced TGI to 38 ± 11%. Groups treated with Vedanta VE800, VE804, and VE411 exhibited TGIs of 77 ± 9, 61 ± 8, and 69%, respectively, whereas treatment with Lactobacillus acidophilus achieved TGIs 57%. VE800 treated mice had significantly increased length of survival compared to mice treated with antibiotics (p = 0.0008, log-rank test). Length of survival was not significantly different between groups with intact gut microbiota and those pretreated with antibiotics and dosed with VE800 (p = 0.52, log-rank test). ICT increased tumor CD4 cells to 11% from 2% and CD8 cells to 9% from 1%., however pre-treatment with antibiotics reduced CD4 cells to 4% and CD8 cells to 1%. Conclusions: Defined consortia of gut microbiota facilitate ICT efficacy. These preclinical studies lay the foundation for optimizing the host response to ICT.

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Pietrzak, Bernadeta, Katarzyna Tomela, Agnieszka Olejnik-Schmidt, Łukasz Galus, Jacek Mackiewicz, Mariusz Kaczmarek, Andrzej Mackiewicz et Marcin Schmidt. « A Clinical Outcome of the Anti-PD-1 Therapy of Melanoma in Polish Patients Is Mediated by Population-Specific Gut Microbiome Composition ». Cancers 14, n^o 21 (31 octobre 2022) : 5369. http://dx.doi.org/10.3390/cancers14215369.

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The gut microbiota is considered a key player modulating the efficacy of immune checkpoint inhibitor therapy. The study investigated the association between the response to anti-PD-1 therapy and the baseline gut microbiome in a Polish cohort of melanoma patients, alongside selected agents modifying the microbiome. Sixty-four melanoma patients enrolled for the anti-PD-1 therapy, and ten healthy subjects were recruited. The response to the treatment was assessed according to the response evaluation criteria in solid tumors, and patients were classified as responders or non-responders. The association between selected extrinsic factors and response was investigated using questionnaire-based analysis and the metataxonomics of the microbiota. In the responders, the Bacteroidota to Firmicutes ratio was higher, and the richness was decreased. The abundance of Prevotella copri and Bacteroides uniformis was related to the response, whereas the non-responders’ gut microbiota was enriched with Faecalibacterium prausnitzii and Desulfovibrio intestinalis and some unclassified Firmicutes. Dietary patterns, including plant, dairy, and fat consumption as well as gastrointestinal tract functioning were significantly associated with the therapeutic effects of the therapy. The specific gut microbiota along with diet were found to be associated with the response to the therapy in the population of melanoma patients.

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Oh, Byeongsang, Frances Boyle, Nick Pavlakis, Stephen Clarke, Thomas Eade, George Hruby, Gillian Lamoury et al. « The Gut Microbiome and Cancer Immunotherapy : Can We Use the Gut Microbiome as a Predictive Biomarker for Clinical Response in Cancer Immunotherapy ? » Cancers 13, n^o 19 (27 septembre 2021) : 4824. http://dx.doi.org/10.3390/cancers13194824.

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Background: Emerging evidence suggests that gut microbiota influences the clinical response to immunotherapy. This review of clinical studies examines the relationship between gut microbiota and immunotherapy outcomes. Method: A literature search was conducted in electronic databases Medline, PubMed and ScienceDirect, with searches for “cancer” and “immunotherapy/immune checkpoint inhibitor” and “microbiome/microbiota” and/or “fecal microbiome transplant FMT”. The relevant literature was selected for this article. Results: Ten studies examined patients diagnosed with advanced metastatic melanoma (n = 6), hepatocellular carcinoma (HCC) (n = 2), non-small cell lung carcinoma (NSCLC) (n = 1) and one study examined combination both NSCLC and renal cell carcinoma (RCC) (n = 1). These studies consistently reported that the gut microbiome profile prior to administering immune checkpoint inhibitors (ICIs) was related to clinical response as measured by progression-free survival (PFS) and overall survival (OS). Two studies reported that a low abundance of Bacteroidetes was associated with colitis. Two studies showed that patients with anti-PD-1 refractory metastatic melanoma experienced improved response rates and no added toxicity when receiving fecal microbiota transplant (FMT) from patients with anti-PD-1 responsive disease. Conclusions: Overall, significant differences in the diversity and composition of the gut microbiome were identified in ICIs responders and non-responders. Our findings provide new insights into the value of assessing the gut microbiome in immunotherapy. Further robust randomized controlled trials (RCTs) examining the modulatory effects of the gut microbiome and FMT on ICIs in patients not responding to immunotherapy are warranted.

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Frankel, Arthur E., Thomas W. Froehlich, Jiwoong Kim, Laura A. Coughlin, Yang Xie, Eugene P. Frenkel et Andrew Y. Koh. « Metagenomic shotgun sequencing to identify specific human gut microbes associated with immune checkpoint therapy efficacy in melanoma patients. » Journal of Clinical Oncology 35, n^o 15_suppl (20 mai 2017) : 9516. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.9516.

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9516 Background: Immune checkpoint inhibitor therapy, ICT, achieves durable remissions in 30-50% of patients (pts) with metastatic melanoma (Larkin et al. NEJM 2015). It is still unclear what host factors modulate response to ICT. Preclinical mouse studies with B16 melanoma demonstrated that ICT response was dependent on the presence of specific commensal gut bacteria (Vetizou et al. Science 2015; Sivan et al. Science2015). These specific gut bacteria induced the maturation of dendritic cells (DCs) and T-cells needed for effective ICT. We sought to determine whether specific gut microbiota are associated with improved response to ICT in melanoma patients. Methods: 37 melanoma pts treated with ICT (nivolumab plus ipilimumab or pembrolizumab alone) at UTSW Medical Center were enrolled. Fecal samples were collected prior to ICT. Genomic DNA was extracted, and metagenomic shotgun sequencing (MSS) performed on an Illumina HiSeq 2500 PE-100. Taxonomic (MetaPhlAn) and functional (HUMAnN) analysis was performed on MSS data. Disease status was assessed by CT scans and physical exams every two months. Results: Among the 23 evaluable pts, 8 were classified as RECIST responders, 5 with stable disease and 10 with progression. RECIST responder microbiomes were significantly enriched with Methanobrevibacter smithii(p = 0.03; LDA coupled with effect size measurements, LEfSe; Kruskal-Wallis test) , Bacteroides thetaiotamicron(p = 0.03) , Lactobacillus plantarum(p = 0.04), and Eubacterium limosum(p = 0.01) compared to those with progressive disease. Conclusions: MSS identified 4 specific gut microbiota associated with improved response to ICT therapy in melanoma pts. All of these bacteria have been shown to modulate host immune response (Bang PLoS One 2014; Hickey Cell Host Microbe 2016; Rigaux Allergy 2009; Kaunachi World J Gastroentertol 2006). To gain mechanistic insight and confirm causality, shotgun metabolomics on the same fecal specimens used for MSS, in vitroimmune cell assays using the gut microbiota identified, and preclinical modeling in a mouse melanoma model with ICT are underway. These studies may lay the foundation for optimizing the host response to ICT.

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Youngster, Ilan, Erez Baruch, Lior Katz, Adi Lahat, Tal Brosh-Nissimov, Jacob Schachter, Omry Koren, Gal Markel et Ben Boursi. « 90. Fecal Microbiota Transplantation in Metastatic Melanoma Patients Resistant to Anti-PD-1 Treatment ». Open Forum Infectious Diseases 6, Supplement_2 (octobre 2019) : S7. http://dx.doi.org/10.1093/ofid/ofz359.014.

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Abstract Background Most metastatic melanoma patients treated with Programed cell Death (PD)-1 blockers fail to achieve a durable response. The gut microbiota profoundly affects host immunity, and fecal microbiota transplantations (FMT) have been shown to enhance anti-PD-1 effectiveness in murine models. We report initial safety and efficacy results from the first patients treated in a Phase I study of FMT and re-induction anti-PD-1 therapy in anti-PD-1 refractory metastatic melanoma. Methods FMT donors were two metastatic melanoma patients who achieved a durable complete response to treatment. FMT recipients were metastatic melanoma patients who failed at least one anti-PD-1 line of treatment. FMT was conducted by both colonoscopic and oral administration, followed by anti-PD-1 re-treatment. Each recipient underwent pre- and post-treatment stool sampling, tissue biopsy of both gut and tumor, and total body imaging. Results Five patients with treatment-resistant metastatic melanoma were recruited. No FMT-related or immunotherapy-related adverse events were observed. To assess engraftment of the new microbiota, recipients were paired with their respective donors and stool 16S rDNA gene sequence analysis was performed. Sequencing results demonstrated post-FMT compositional dissimilarity (Unweighted UniFrac, P = 0.04, FDR q = 0.22) between the two recipient–donor groups. Specific taxonomic dynamics included post-FMT increased abundance of Paraprevotellaceae, previously associated in descriptive studies with responsiveness to treatment, and significant reductions in abundance of β-proteobacteria, previously associated with reduced response to treatment. Immunohistochemical stains of biopsies demonstrated an increased post-FMT infiltration of antigen presenting cells (CD68+) in the gut (paired T-test, P = 0.008) and in the tumor (P = 0.0076). Post-treatment intra-tumoral CD8+ T-cell infiltration was also increased. Three patients had a partial or complete response to treatment post-FMT. Conclusion FMT in metastatic melanoma patients seems to be safe and may alter recipient gut microbiota to resemble that of a responder donor. This alteration may result in intra-tumoral T-cell activity, and conferred clinical and radiological benefit in several recipients previously unresponsive to treatment. Disclosures All Authors: No reported Disclosures.

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Spencer, Christine N., Jennifer L. McQuade, Vancheswaran Gopalakrishnan, John A. McCulloch, Marie Vetizou, Alexandria P. Cogdill, Md A. Wadud Khan et al. « Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response ». Science 374, n^o 6575 (24 décembre 2021) : 1632–40. http://dx.doi.org/10.1126/science.aaz7015.

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Another benefit of dietary fiber The gut microbiome can modulate the immune system and influence the therapeutic response of cancer patients, yet the mechanisms underlying the effects of microbiota are presently unclear. Spencer et al . add to our understanding of how dietary habits affect microbiota and clinical outcomes to immunotherapy. In an observational study, the researchers found that melanoma patients reporting high fiber (prebiotic) consumption had a better response to checkpoint inhibitor immunotherapy compared with those patients reporting a low-fiber diet. The most marked benefit was observed for those patients reporting a combination of high fiber consumption and no use of over-the-counter probiotic supplements. These findings provide early insights as to how diet-related factors may influence the immune response. —PNK

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Guardamagna, Mora, Miguel-Angel Berciano-Guerrero, Beatriz Villaescusa-González, Elisabeth Perez-Ruiz, Javier Oliver, Rocío Lavado-Valenzuela, Antonio Rueda-Dominguez, Isabel Barragán et María Isabel Queipo-Ortuño. « Gut Microbiota and Therapy in Metastatic Melanoma : Focus on MAPK Pathway Inhibition ». International Journal of Molecular Sciences 23, n^o 19 (9 octobre 2022) : 11990. http://dx.doi.org/10.3390/ijms231911990.

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Gut microbiome (GM) and its either pro-tumorigenic or anti-tumorigenic role is intriguing and constitutes an evolving landscape in translational oncology. It has been suggested that these microorganisms may be involved in carcinogenesis, cancer treatment response and resistance, as well as predisposition to adverse effects. In melanoma patients, one of the most immunogenic cancers, immune checkpoint inhibitors (ICI) and MAPK-targeted therapy—BRAF/MEK inhibitors—have revolutionized prognosis, and the study of the microbiome as a modulating factor is thus appealing. Although BRAF/MEK inhibitors constitute one of the main backbones of treatment in melanoma, little is known about their impact on GM and how this might correlate with immune re-induction. On the contrary, ICI and their relationship to GM has become an interesting field of research due to the already-known impact of immunotherapy in modulating the immune system. Immune reprogramming in the tumor microenvironment has been established as one of the main targets of microbiome, since it can induce immunosuppressive phenotypes, promote inflammatory responses or conduct anti-tumor responses. As a result, ongoing clinical trials are evaluating the role of fecal microbiota transplant (FMT), as well as the impact of using dietary supplements, antibiotics and probiotics in the prediction of response to therapy. In this review, we provide an overview of GM’s link to cancer, its relationship with the immune system and how this may impact response to treatments in melanoma patients. We also discuss insights about novel therapeutic approaches including FMT, changes in diet and use of probiotics, prebiotics and symbiotics. Finally, we hypothesize on the possible pathways through which GM may impact anti-tumor efficacy in melanoma patients treated with targeted therapy, an appealing subject of which little is known.

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Vandoni, G., F. D’Amico, S. Turroni, P. Brigidi, S. Sieri, A. Casirati, G. Borghese, L. Di Guardo et C. Gavazzi. « Diet and gut microbiota analysis in patients with advanced melanoma undergoing immunotherapy ». Clinical Nutrition ESPEN 46 (décembre 2021) : S707. http://dx.doi.org/10.1016/j.clnesp.2021.09.463.

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Johnson, Sarah, Golnaz Morad, Nadim Ajami, Jennifer Wargo, Matthew Wong et Matthew Lastrapes. « 838 The role of microbiota in metastatic brain tumors ». Journal for ImmunoTherapy of Cancer 9, Suppl 2 (novembre 2021) : A879. http://dx.doi.org/10.1136/jitc-2021-sitc2021.838.

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BackgroundDespite the substantial advances in the treatment of systemic cancer, brain metastases are still responsible for significant morbidity and mortality, necessitating a better understanding of the mechanisms underlying this disease. Microbiota has emerged as a significant hallmark of cancer. Our group and others have demonstrated a prominent role for gut and intratumoral microbiota in tumorigenesis, tumor immunity, and response to treatment. However, the role of microbiota in brain metastasis is poorly understood. We hypothesize that distinct microbial communities can alter the immune microenvironment in the brain and modulate the different steps of brain metastasis formation.MethodsTo explore the role of microbiota in brain metastasis, we evaluated the gut and oral microbial signatures in brain metastasis patients through shotgun metagenomics sequencing. Furthermore, we conducted mechanistic in vivo studies in which the gut microbiota was depleted in conventionally raised mice using a broad-spectrum non-absorbable antibiotic regimen. Subsequently, melanoma tumor cells were injected intracranially to evaluate the effect of gut microbiota depletion and associated immune changes on tumor growth. Tumor growth was measured through in vivo bioluminescent imaging and histology. Peripheral and tumor immune profiling was conducted through flow cytometry and immunohistochemistry.ResultsOur clinical studies demonstrated the enrichment of distinct bacterial and viral taxa within the gut and oral microbiota in brain metastasis patients. Depletion of the gut microbiota in mice decreased tumor growth in the brain. Evaluation of the peripheral and tumor immune profiles suggested the underlying mechanisms to involve alterations in the circulating cytokine profiles and an increase in anti-tumor T cell activity.ConclusionsOur clinical studies suggest the association of distinct microbial communities with brain metastasis. Our pre-clinical findings demonstrate that the absence of gut microbiota can modulate the regulation of T cell activity to induce an anti-tumor response in the brain. Further studies, currently in progress, will determine the mechanistic role of dysbiotic microbiota and distinct microbial communities in this process.AcknowledgementsThis work was supported by the National Institute of Health (1F32CA260769-01).

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Fedorov, D. E., E. I. Olekhnovich, A. V. Pavlenko, K. M. Klimina, I. A. Pokataev, A. I. Manolov, D. N. Konanov, V. A. Veselovsky et E. N. Ilina. « Intestinal microbiome as a predictor of the anti-PD-1 therapy success : metagenomic data analysis ». Biomeditsinskaya Khimiya 66, n^o 6 (2020) : 502–7. http://dx.doi.org/10.18097/pbmc20206606502.

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Anti-PD-1 immunotherapy has a large impact on cancer treatment but the rate of positive treatment outcomes is 40-45% and depends on many factors. One of the factors affecting the outcome of immunotherapy is the gut microbiota composition. This effect has been demonstrated both in model objects and in clinical patients groups. However, in order to identify clear causal relationships between microbiota and anti-PD1 immunotherapy response, it is necessary to expand the number of patients and experimental samples. This work presents an analysis of metagenomic data obtained using whole-genome sequencing of stool samples from melanoma patients (n=45) with different responses to anti-PD1 therapy. The analysis of the differential representation of microbial species has shown a difference in the composition of the microbiota between the experimental groups. Results of this study indicate existence of a strong link between the composition of the gut microbiota and the outcome of anti-PD1 therapy. Expansion of similar research may help develop additional predictive tools for the outcome of anti-PD1 cancer immunotherapy, as well as increase its effectiveness.

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Rossi, Marco, Salvatore M. Aspromonte, Frederick J. Kohlhapp, Jenna H. Newman, Alex Lemenze, Russell J. Pepe, Samuel M. DeFina et al. « Gut Microbial Shifts Indicate Melanoma Presence and Bacterial Interactions in a Murine Model ». Diagnostics 12, n^o 4 (12 avril 2022) : 958. http://dx.doi.org/10.3390/diagnostics12040958.

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Through a multitude of studies, the gut microbiota has been recognized as a significant influencer of both homeostasis and pathophysiology. Certain microbial taxa can even affect treatments such as cancer immunotherapies, including the immune checkpoint blockade. These taxa can impact such processes both individually as well as collectively through mechanisms from quorum sensing to metabolite production. Due to this overarching presence of the gut microbiota in many physiological processes distal to the GI tract, we hypothesized that mice bearing tumors at extraintestinal sites would display a distinct intestinal microbial signature from non-tumor-bearing mice, and that such a signature would involve taxa that collectively shift with tumor presence. Microbial OTUs were determined from 16S rRNA genes isolated from the fecal samples of C57BL/6 mice challenged with either B16-F10 melanoma cells or PBS control and analyzed using QIIME. Relative proportions of bacteria were determined for each mouse and, using machine-learning approaches, significantly altered taxa and co-occurrence patterns between tumor- and non-tumor-bearing mice were found. Mice with a tumor had elevated proportions of Ruminococcaceae, Peptococcaceae.g_rc4.4, and Christensenellaceae, as well as significant information gains and ReliefF weights for Bacteroidales.f__S24.7, Ruminococcaceae, Clostridiales, and Erysipelotrichaceae. Bacteroidales.f__S24.7, Ruminococcaceae, and Clostridiales were also implicated through shifting co-occurrences and PCA values. Using these seven taxa as a melanoma signature, a neural network reached an 80% tumor detection accuracy in a 10-fold stratified random sampling validation. These results indicated gut microbial proportions as a biosensor for tumor detection, and that shifting co-occurrences could be used to reveal relevant taxa.

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Chaput, N., P. Lepage, C. Coutzac, E. Soularue, K. Le Roux, C. Monot, L. Boselli et al. « Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab ». Annals of Oncology 28, n^o 6 (juin 2017) : 1368–79. http://dx.doi.org/10.1093/annonc/mdx108.

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Chaput, N., P. Lepage, C. Coutzac, E. Soularue, K. Le Roux, C. Monot, L. Boselli et al. « Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab ». Annals of Oncology 30, n^o 12 (décembre 2019) : 2012. http://dx.doi.org/10.1093/annonc/mdz224.

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Tomela, Katarzyna, Bernadeta Pietrzak, Marcin Schmidt et Andrzej Mackiewicz. « The Tumor and Host Immune Signature, and the Gut Microbiota as Predictive Biomarkers for Immune Checkpoint Inhibitor Response in Melanoma Patients ». Life 10, n^o 10 (25 septembre 2020) : 219. http://dx.doi.org/10.3390/life10100219.

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There are various melanoma treatment strategies that are based on immunological responses, among which immune checkpoint inhibitors (ICI) are relatively novel form. Nowadays, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies represent a standard treatment for metastatic melanoma. Although there are remarkable curative effects in responders to ICI therapy, up to 70% of melanoma patients show resistance to this treatment. This low response rate is caused by innate as well as acquired resistance, and some aspects of treatment resistance are still unknown. Growing evidence shows that gut microbiota and bacterial metabolites, such as short-chain fatty acids (SCFAs), affect the efficacy of immunotherapy. Various bacterial species have been indicated as potential biomarkers of anti-PD-1 or anti-CTLA-4 therapy efficacy in melanoma, next to biomarkers related to molecular and genetic tumor characteristics or the host immunological response, which are detected in patients’ blood. Here, we review the current status of biomarkers of response to ICI melanoma therapies, their pre-treatment predictive values, and their utility as on-treatment monitoring tools in order to select a relevant personalized therapy on the basis of probability of the best clinical outcome.

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Chaput, N., P. Lepage, C. Coutzac, E. Soularue, V. Asvatourian, E. Lanoy, C. Mateus, F. Carbonnel et C. Robert. « Baseline gut microbiota in metastatic melanoma patients treated with ipilimumab : Relation with clinical response and colitis ». Annals of Oncology 28 (septembre 2017) : v28—v29. http://dx.doi.org/10.1093/annonc/mdx363.021.

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Wang, Feng. « Bifidobacterium improves the outcome of immune checkpoint blockade by modulating Treg cell function ». Journal of Immunology 204, n^o 1_Supplement (1 mai 2020) : 90.2. http://dx.doi.org/10.4049/jimmunol.204.supp.90.2.

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Abstract Immune checkpoint-blocking antibodies that attenuate immune tolerance have been used to effectively treat cancer, but they can also trigger severe immune-related adverse events. Previously, we found that Bifidobacterium could mitigate intestinal immunopathology in the context of CTLA-4 blockade in mice. Here, we examined the mechanism underlying this process. We found that Bifidobacterium altered the composition of the gut microbiota systematically in a regulatory T cell (Treg)-dependent manner. Moreover, this altered commensal community enhanced both the metabolic and suppressive functions of intestinal Treg cells, contributing to the amelioration of colitis during CTLA-4 blockade. Importantly, Bifidobacterium ameliorated gut immunopathology and boosted anti-melanoma immunity with combination therapy of anti-CTLA-4 and anti-PD-L1.

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Peng, Zhi, Xiaotian Zhang, Tong Xie, Siyuan Cheng, Zihan Han, Shulin Wang, Zongwen Ban et al. « Efficacy of fecal microbiota transplantation in patients with anti-PD-1–resistant/refractory gastrointestinal cancers. » Journal of Clinical Oncology 41, n^o 4_suppl (1 février 2023) : 389. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.389.

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389 Background: Gut microbiome that changed the response to anti-PD-1 therapy (aPD-1) against melanoma by fecal microbiota transplantation (FMT) has been reported. To investigate whether resistance to aPD-1 against gastrointestinal (GI) cancers can be overcome by FMT, this single arm, open label, investigator-initiated trial explored the efficacy of combination of FMT + nivolumab in patients with aPD-1 resistant/refractory (aPD-1r)-GI cancers. Methods: Ten patients were planned to be enrolled. Interim analysis was planned when at least one patient demonstrated effective outcome. FMT capsules were from healthy donors. FMT capsules (CFU≥1×1012) were administered in the first week. Nivolumab (3mg/kg, q2w) combined with a maintenance dose of FMT capsules (CFU≥1.5×1011) were started at Week 2 and continued for 6 cycles or until progress of disease (PD) after 3 cycles of treatment. If patient responded to the treatment and would be benefit from the treatment beyond 6 cycles, patients would enter the Expended Excess Program to continue the therapy. RECIST v1.1 evaluation was performed every 3 cycles. Stool samples were collected every 2 weeks for metagenomic analysis of gut microbiota. Results: 8 aPD-1r patients were enrolled and finished the study by the time of this analysis. Nivolumab + FMT therapy was well tolerated. No serious adverse reaction was observed. 8 patients completed 3 cycles of treatment. Metagenomic analysis of gut microbiota from Responders (R) and Non-Responders (NR) groups revealed the gut microbial composition of R group is significantly closer to that of the donor than NR group, which indicated much better colonization of donor microbiota in R. Alpha diversity was significantly higher in R than that in NR, along with a set of differential bacterial species and biological process functions including dTMP biosynthetic process enriched, suggesting gut microbiome’s potential role in the treatment. The flow cytometry analysis indicated a significant increase of IFN-ϒ+ cells in PBMCs in R at Day 8 after FMT (the highest increase during the study), before combination therapy had started. A significant increase in Ki-67+ cells in PBMCs was also observed in the R group. Relative abundance of differential bacterial species enriched in R were found to be significantly negative correlated with tumor markers like CA199 and tumor volume, and some were positively correlated with expression of CD3+CD4+ cells and CD3+CD8+ cells. Conclusions: FMT+aPD-1 may overcome the resistance to aPD-1 against GI cancer via changing gut microbiota structure. Trial registration number: NCT04130763. Keywords: gastrointestinal cancers; fecal microbiota transplantation; anti-PD-1 therapy. Clinical trial information: NCT04130763 .

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Ferrucci, Pier Francesco, et Emilia Cocorocchio. « Novel Biomarkers and Druggable Targets in Advanced Melanoma ». Cancers 14, n^o 1 (24 décembre 2021) : 81. http://dx.doi.org/10.3390/cancers14010081.

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Immunotherapy with Ipilimumab or antibodies against programmed death (ligand) 1 (anti-PD1/PDL1), targeted therapies with BRAF-inhibitors (anti-BRAF) and their combinations significantly changed melanoma treatment options in both primary, adjuvant and metastatic setting, allowing for a cure, or at least long-term survival, in most patients. However, up to 50% of those with advance or metastatic disease still have no significant benefit from such innovative therapies, and clinicians are not able to discriminate in advance neither who is going to respond and for how long nor who is going to develop collateral effects and which ones. However, druggable targets, as well as affordable and reliable biomarkers are needed to personalize resources at a single-patient level. In this manuscript, different molecules, genes, cells, pathways and even combinatorial algorithms or scores are included in four biomarker chapters (molecular, immunological, peripheral and gut microbiota) and reviewed in order to evaluate their role in indicating a patient’s possible response to treatment or development of toxicities.

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Miller, Wilson H., Bertrand Routy, Rahima Jamal, D. Scott Ernst, Diane Logan, Khashayar Esfahani, Karl Belanger et al. « Fecal microbiota transplantation followed by anti–PD-1 treatment in patients with advanced melanoma. » Journal of Clinical Oncology 40, n^o 16_suppl (1 juin 2022) : 9533. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.9533.

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9533 Background: The gut microbiome has been shown to be a biomarker of response in patients (pts) with melanoma. Strategies to modify the microbiome are currently being investigated. We report the effects of Fecal Microbiota Transplantation (FMT) on safety and anti-PD-1 response in pts with melanoma from a phase I trial (NCT03772899). Methods: 20 pts with advanced melanoma with RECIST-evaluable disease, without prior anti-PD-1 treatment for advanced disease, were recruited from 3 Canadian academic centers. Pts with ECOG > 2, autoimmune diseases, immunosuppression or unstable brain metastases were excluded. Pts received 80-100 g of healthy donor stool via oral capsules and were treated with anti-PD-1 one week later. The primary objective was safety of combining FMT with anti-PD-1 therapy. Objective response rate (ORR) by RECIST 1.1 and correlative studies were secondary objectives. Flow cytometry and multiplex ELISA were performed on pts blood samples. Avatar mice were transplanted with stool samples obtained from participants on the trial before and after FMT. Mice were subsequently implanted with B-16 or MCA-205 tumors and received anti-PD-1 antibodies. Results: Median age was 75.5 years, 12 (60%) were male, 18 (90%) had stage 4 disease, and 5 (25%) pts harbored a BRAF mutation. Median follow-up was 11.2 months. FMT-related adverse events included grade 2 diarrhea (2 pts) and hypophosphatemia (1 pt), and 13 pts (65%) experienced grade 1 gastrointestinal toxicities. Grade 3 immune-related adverse events (irAE) were one each of myocarditis, nephritis, and fatigue. Anti-PD-1 therapy was discontinued for toxicity in 2 (10%) pts. No unexpected irAE or death on treatment occurred. ORR was 65% (13/20), of which 3 were CR. Clinical benefit rate (includes SD lasting > 6 months) was 75% (15/20). Median PFS was not reached, and one pt died from their disease. Translational analyses demonstrated upregulation of IL-17 post-FMT in responders, which correlated with upregulation of the frequency of Th17 cells in peripheral blood. In parallel, murine experiments showed that feces from pts pre-FMT did not sensitize tumors to anti-PD-1. In both tumor models, only feces obtained post-FMT from responders restored anti-PD-1 efficacy in mice, providing strong support that FMT contributed to the anti-tumor response observed in pts. Conclusions: FMT followed by anti-PD-1 treatment in melanoma pts undergoing therapy is safe and may lead to improved anti-tumor responses that can be reproduced in tumor mouse models. The gut microbiome plays an important role in responses to anti-PD-1 in patients with advanced melanoma, paving the way for future microbiome-based interventions. Clinical trial information: NCT03772899.

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Lam, Khiem C., April Huang, Romina E. Araya, Quanyi Chen et Romina S. Goldszmid. « Tumor-intrinsic factors dictate beneficial effect of microbiota-based therapies ». Journal of Immunology 208, n^o 1_Supplement (1 mai 2022) : 120.08. http://dx.doi.org/10.4049/jimmunol.208.supp.120.08.

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Abstract Gut microbiota impacts antitumor immunity and recent studies have shown that manipulating microbiota via fecal transplant can rescue immune checkpoint blockade (ICB) response in refractory melanoma patients. However, not all patients benefited from this approach. We hypothesize that tumor-intrinsic factors (e.g. neoantigen load and immune microenvironment) contribute to the microbiota effect on anticancer response. To test this, we performed preclinical microbiota manipulation studies using dietary intervention. Mice fed high-fiber diet (FD) had improved spontaneous tumor control and response to ICB. Mechanistically, FD-induced changes in microbiota composition skewed the tumor innate immune repertoire towards an antitumor profile marked by increased dendritic cell infiltration. Downstream of the innate compartment, FD reduced the proportion of intratumoral Tregs and exhausted CD8+ T cells. We further assessed the effects of FD across 8 tumor models including EL4 lymphoma, MC38 colon carcinoma, and 6 melanomas (M1–M6) that mimic the variety of human melanoma subtypes. Although FD had a beneficial effect overall, not all models responded to the same extent, and were accompanied by different changes in the tumor immune profile. FD delayed tumor initiation for EL4 and M4, reduced growth rate for M3 and M5, both delayed initiation and reduced growth rate for MC38, M2, and M6, but had no significant effects for M1. Additionally, we found that increasing tumor immunogenicity resulted in a synergistic effect with FD. Our data suggests that tumor-intrinsic factors influence the beneficial effect of microbiota on antitumor immunity. Identifying these factors will help refine the use of microbiota-based therapies in the clinic. This research was supported by the Intramural Research Program of the NIH (CCR-NCI). This research was supported by the Intramural Research Program of the NIH (CCR-NCI).

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Li, J., L. Xu, Z. Peng, H. Jiang, F. Chao, Y. Ding, J. M. Moll et al. « 841P Effects of immune checkpoint inhibitor-based combination therapies on the gut microbiota in advanced melanoma patients ». Annals of Oncology 33 (septembre 2022) : S934. http://dx.doi.org/10.1016/j.annonc.2022.07.967.

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Veziant, Julie, Romain Villéger, Nicolas Barnich et Mathilde Bonnet. « Gut Microbiota as Potential Biomarker and/or Therapeutic Target to Improve the Management of Cancer : Focus on Colibactin-Producing Escherichia coli in Colorectal Cancer ». Cancers 13, n^o 9 (5 mai 2021) : 2215. http://dx.doi.org/10.3390/cancers13092215.

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The gut microbiota is crucial for physiological development and immunological homeostasis. Alterations of this microbial community called dysbiosis, have been associated with cancers such colorectal cancers (CRC). The pro-carcinogenic potential of this dysbiotic microbiota has been demonstrated in the colon. Recently the role of the microbiota in the efficacy of anti-tumor therapeutic strategies has been described in digestive cancers and in other cancers (e.g., melanoma and sarcoma). Different bacterial species seem to be implicated in these mechanisms: F. nucleatum, B. fragilis, and colibactin-associated E. coli (CoPEC). CoPEC bacteria are prevalent in the colonic mucosa of patients with CRC and they promote colorectal carcinogenesis in susceptible mouse models of CRC. In this review, we report preclinical and clinical data that suggest that CoPEC could be a new factor predictive of poor outcomes that could be used to improve cancer management. Moreover, we describe the possibility of using these bacteria as new therapeutic targets.

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Weinberg, Frank, Robert P. Dickson, Deepak Nagrath et Nithya Ramnath. « The Lung Microbiome : A Central Mediator of Host Inflammation and Metabolism in Lung Cancer Patients ? » Cancers 13, n^o 1 (22 décembre 2020) : 13. http://dx.doi.org/10.3390/cancers13010013.

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Lung cancer is the leading cause of cancer-related death. Over the past 5–10 years lung cancer outcomes have significantly improved in part due to better treatment options including immunotherapy and molecularly targeted agents. Unfortunately, the majority of lung cancer patients do not enjoy durable responses to these new treatments. Seminal research demonstrated the importance of the gut microbiome in dictating responses to immunotherapy in melanoma patients. However, little is known regarding how other sites of microbiota in the human body affect tumorigenesis and treatment responses. The lungs were traditionally thought to be a sterile environment; however, recent research demonstrated that the lung contains its own dynamic microbiota that can influence disease and pathophysiology. Few studies have explored the role of the lung microbiome in lung cancer biology. In this review article, we discuss the links between the lung microbiota and cancer, with particular focus on immune responses, metabolism and strategies to target the lung microbiome for cancer prevention.

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Tsunoda, Takuya, Kazunori Shimada, Naoki Uchida, Shinichi Kobayashi et Yasutsuna Sasaki. « Dynamic relationships among tumor, immune response, and microbiota ». Trends in Immunotherapy 3, n^o 1 (4 mai 2019) : 41. http://dx.doi.org/10.24294/ti.v3.i1.79.

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Recently, the analysis of microbiota has been of interest not only for the clarification of the molecular mechanisms of disease etiology, but also the discovery of novel strategies for treatment. Following the development of "next-generation" sequencing, novel areas have been discovered in microbiota; however, in oncology, the relationships between microbiota and cancer have not been fully clarified. In recent literature, surprisingly, detection of gut microbiota in tumor issue itself has been reported. Microbiota might play an important role in carcinogenesis. However, this phenomenon is not well understood, and research in this area has just begun. In the past five years, a paradigm shift has occurred in cancer treatment due to immunotherapy. Immunotherapy has made cure possible even in advanced cancer patients with not only melanoma but also non-small cell lung cancer and others. In this review, we discuss the mechanisms of novel immunotherapies, checkpoint inhibitors, and the relationship between microbiota and immunotherapy. It is of significance to clarify this relationship because it may lead to the discovery of predictive markers for immunotherapy and promote clinical efficacy. Finally, we also mention our activities in the construction of a big database for information on immunotherapy and microbiota, which may lead to excellent possibilities of discovering novel strategies for more effective cancer treatments, and may accelerate the alteration of cancers to the classification of chronic nonfatal disease.

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Robinson, Matthew, Kevin Vervier, Simon Harris, David Adams, Doreen Milne, Catherine Booth, Emily Barker et al. « 673 Precision microbiome mapping identifies a microbiome signature predictive of Immune checkpoint inhibitor response across multiple research study cohorts ». Journal for ImmunoTherapy of Cancer 8, Suppl 3 (novembre 2020) : A711. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0673.

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BackgroundThe gut microbiome of cancer patients appears to be associated with response to Immune Checkpoint Inhibitor (ICIs) treatment.1–4 However, the bacteria linked to response differ between published studies.MethodsLongitudinal stool samples were collected from 69 patients with advanced melanoma receiving approved ICIs in the Cambridge (UK) MELRESIST study. Pretreatment samples were analysed by Microbiotica, using shotgun metagenomic sequencing. Microbiotica’s sequencing platform comprises the world’s leading Reference Genome Database and advanced Microbiome Bioinformatics to give the most comprehensive and precise mapping of the gut microbiome. This has enabled us to identify gut bacteria associated with ICI response missed using public reference genomes. Published microbiome studies in advanced melanoma,1–3renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC)4 were reanalysed with the same platform.ResultsAnalysis of the MELRESIST samples showed an overall change in the microbiome composition between advanced melanoma patients and a panel of healthy donor samples, but not between patients who subsequently responded or did not respond to ICIs. However, we did identify a discrete microbiome signature which correlated with response. This signature predicted response with an accuracy of 93% in the MELRESIST cohort, but was less predictive in the published melanoma cohorts.1–3 Therefore, we developed a bioinformatic analytical model, incorporating an interactive random forest model and the MELRESIST dataset, to identify a microbiome signature which was consistent across all published melanoma studies. This model was validated three times by accurately predicting the outcome of an independent cohort. A final microbiome signature was defined using the validated model on MELRESIST and the three published melanoma cohorts. This was very accurate at predicting response in all four studies combined (91%), or individually (82–100%). This signature was also predictive of response in a NSCLC study and to a lesser extent in RCC. The core of this signature is nine bacteria significantly increased in abundance in responders.ConclusionsAnalysis of the MELRESIST study samples, precision microbiome profiling by the Microbiotica Platform and a validated bioinformatic analysis, have enabled us to identify a unique microbiome signature predictive of response to ICI therapy in four independent melanoma studies. This removes the challenge to the field of different bacteria apparently being associated with response in different studies, and could represent a new microbiome biomarker with clinical application. Nine core bacteria may be driving response and hold potential for co-therapy with ICIs.Ethics ApprovalThe study was approved by Newcastle & North Tyneside 2 Research Ethics Committee, approval number 11/NE/0312.ReferencesMatson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018;359(6371):104–108.Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359(6371):97–103.Frankel AE, Coughlin LA, Kim J, et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia 2017;19(10):848–855.Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359(6371):91–97.

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Chen, Lili, Xinyu Zhou, Yawei Wang, Dake Wang, Yueshuang Ke et Xianlu Zeng. « Propionate and Butyrate Produced by Gut Microbiota after Probiotic Supplementation Attenuate Lung Metastasis of Melanoma Cells in Mice ». Molecular Nutrition & ; Food Research 65, n^o 15 (18 juin 2021) : 2100096. http://dx.doi.org/10.1002/mnfr.202100096.

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Dees, Kory, Hyunmin Koo, James Humphreys, Joseph Hakim, David Crossman, Michael Crowley, L. Burt Nabors, Etty Benveniste, Casey Morrow et Braden McFarland. « IMMU-09. HUMAN MICROBIOTA INFLUENCE THE EFFICACY OF IMMUNOTHERAPY IN A MOUSE MODEL OF GLIOBLASTOMA ». Neuro-Oncology 23, Supplement_6 (2 novembre 2021) : vi93—vi94. http://dx.doi.org/10.1093/neuonc/noab196.369.

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Abstract Although immunotherapy works well in glioblastoma (GBM) pre-clinical mouse models, the therapy has unfortunately not demonstrated efficacy in humans. In melanoma and other cancers, the composition of the gut microbiome has been shown to determine responsiveness or resistance to immune checkpoint inhibitors (anti-PD-1). Most pre-clinical cancer studies have been done in mouse models using mouse gut microbiomes, but there are significant differences between mouse and human microbial gut compositions. To address this inconsistency, we developed a novel humanized microbiome (HuM) model to study the response to immunotherapy in a pre-clinical mouse model of GBM. We used five healthy human donors for fecal transplantation of gnotobiotic mice. After the transplanted microbiomes stabilized, the mice were bred to generate five independent humanized mouse lines (HuM1-HuM5). Analysis of shotgun metagenomic sequencing data from fecal samples revealed a unique microbiome with significant differences in diversity and microbial composition among HuM1-HuM5 lines. Interestingly, we found that the HuM lines responded differently to anti-PD-1. Specifically, we demonstrate that HuM2 and HuM3 mice are responsive to anti-PD-1 and displayed significantly increased survival compared to isotype controls, while HuM1, HuM4, and HuM5 mice are resistant to anti-PD-1. These mice are genetically identical, and only differ in the composition of the gut microbiome. In a correlative experiment, we found that disrupting the responder HuM2 microbiome with antibiotics abrogated the positive response to anti-PD-1, indicating that HuM2 microbiota must be present in the mice to elicit the positive response to anti-PD-1 in the GBM model. The question remains of whether the “responsive” microbial communities in HuM2 and HuM3 can be therapeutically exploited and applicable in other tumor models, or if the “resistant” microbial communities in HuM1, HuM4, and HuM5 can be depleted and/or replaced. Future studies will assess responder microbial transplants as a method of enhancing immunotherapy.

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Lee, Pei-Chang, Chi-Jung Wu, Ya-Wen Hung, Chieh-Ju Lee, Yee Chao, Ming-Chih Hou, Yu-Lun Kuo, Shih-Hsuan Chou et Yi-Hsiang Huang. « Association of gut microbiota and metabolites with tumor response to immune checkpoint inhibitors in patients with unresectable hepatocellular carcinoma. » Journal of Clinical Oncology 39, n^o 15_suppl (20 mai 2021) : e16165-e16165. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e16165.

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e16165 Background: Immunotherapy with checkpoint inhibitors (ICI) is a promising treatment for unresectable hepatocellular carcinoma (HCC), but lack of effective biomarker to predict treatment response. Gut microbiome could modulate tumor response to immunotherapy in melanoma; but its effects on HCC are still unclear. Methods: From May 2018 to April 2020, 94 patients received ICI treatment for unresectable HCC (uHCC) in Taipei Veterans General Hospital, the feces samples were prospectively collected before ICI treatment. Finally, 20 patients with radiology proven objective tumor responses (OR; 3 complete responses and 17 partial responses) following immunotherapy, and 21 randomly selected patients with progressive disease (PD) were enrolled for fecal microbiota and metabolites investigation. In addition, feces from 17 healthy volunteers were taken as normal control. Results: Although the alpha diversity was not significantly different among groups, the principal component analysis of Bray-Curtis distance showed a significant clustering of fecal microbiota between HCC patients and healthy volunteers. The significant bacterial dissimilarity was observed between OR and PD patients following immunotherapy (p = 0.016 and 0.019 by Anoism and Adonis tests, respectively). According to linear discriminant analysis (LDA) effect size (LEfSe), a prominence of Prevotella usually regarded as a pathogenic bacterium, was more abundant in HCC patients with PD to ICI treatment. While Veillonella, Lachnospiraceae, Lachnoclostridium, Lactobacillales, Streptococcaceae and Ruminococcaceae were predominant in patients with OR (LDA score [log10] > 3). In addition, primary bile acids, including murocholic acid, α and β-muricholic acids, and secondary bile acids, including ursodeoxycholic acid, ursocholic acid, tauro-ursodeoxycholic acid, and taurohyocholic acid were significantly dominant in the feces of patients with OR to ICI treatment. Correlation network analysis in patients with OR showed significant linkages between Lachnoclostridium, Ruminococcus and secondary bile acids. Conclusions: Fecal microbiota and bile acids are associated with the response to immunotherapy for uHCC patients. These findings highlight the potential role of microbiota as a biomarker and strategy to enhance response to immunotherapy by modifying gut microbiota for uHCC.

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Zuccaro, Valentina, Andrea Lombardi, Erika Asperges, Paolo Sacchi, Piero Marone, Alessandra Gazzola, Luca Arcaini et Raffaele Bruno. « The Possible Role of Gut Microbiota and Microbial Translocation Profiling During Chemo-Free Treatment of Lymphoid Malignancies ». International Journal of Molecular Sciences 20, n^o 7 (9 avril 2019) : 1748. http://dx.doi.org/10.3390/ijms20071748.

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The crosstalk between gut microbiota (GM) and the immune system is intense and complex. When dysbiosis occurs, the resulting pro-inflammatory environment can lead to bacterial translocation, systemic immune activation, tissue damage, and cancerogenesis. GM composition seems to impact both the therapeutic activity and the side effects of anticancer treatment; in particular, robust evidence has shown that the GM modulates the response to immunotherapy in patients affected by metastatic melanoma. Despite accumulating knowledge supporting the role of GM composition in lymphomagenesis, unexplored areas still remain. No studies have been designed to investigate GM alteration in patients diagnosed with lymphoproliferative disorders and treated with chemo-free therapies, and the potential association between GM, therapy outcome, and immune-related adverse events has never been analyzed. Additional studies should be considered to create opportunities for a more tailored approach in this set of patients. In this review, we describe the possible role of the GM during chemo-free treatment of lymphoid malignancies.

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Oey, Oliver, Yu-Yang Liu, Angela Felicia Sunjaya, Daniel Martin Simadibrata, Muhammad Adnan Khattak et Elin Gray. « Gut microbiota diversity and composition in predicting immunotherapy response and immunotherapy-related colitis in melanoma patients : A systematic review ». World Journal of Clinical Oncology 13, n^o 11 (24 novembre 2022) : 929–42. http://dx.doi.org/10.5306/wjco.v13.i11.929.

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Maleki, Saman, John Lenehan, Jeremy Burton, Michael Silverman, Seema Nair Parvathy, Mikal El-Hajjar et Mithunah Krishnamoorthy. « P864 Combination of fecal microbiota transplantation from healthy donors with anti-PD1 immunotherapy in treatment-naïve advanced or metastatic melanoma patients ». Journal for ImmunoTherapy of Cancer 8, Suppl 1 (avril 2020) : A11—A12. http://dx.doi.org/10.1136/lba2019.17.

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BackgroundCheckpoint inhibitors have changed the outcomes for patients with advanced melanoma. However, many patients still show primary resistance to single-agent therapy. Recently, the role of the gut microbiome in influencing antitumor immunity has been established. Currently, various methods of modifying the gut microbiome of cancer patients are being explored. We report the initial safety results of the first two patients treated on a phase I study combining Fecal Microbiota Transplantation (FMT) with single-agent anti-PD1 in treatment-naïve patients with advanced melanoma.MethodsTwo healthy donors were selected through our screening process and approximately 100 grams of fresh stool was processed and prepared for FMT as per our standardized protocol. FMT recipients were melanoma patients with unresectable or metastatic disease who were treatment naïve for their advanced disease. Bowel preparation was completed the day prior and FMT was performed using oral administration of approximately 40 capsules. Anti-PD1 was started at least 1 week after FMT to allow for microbiome engraftment. Blood and stool were analyzed at baseline (pre-FMT), before immunotherapy, and three weeks after it.ResultsPatient 1 was diagnosed with recurrent melanoma of the lower limb with multiple in-transit lesions refractory to control with surgery and a single intralesional injection of IL-2. Patient received stool from Donor 1 and did not experience any adverse effects from FMT. At the time of treatment #4, a solitary large cutaneous lesion stabilized but the patient experienced grade 1 diarrhoea, grade 2 nausea, and grade 2 fatigue, and grade 2 depression (NCI-CTCAE v5.0). Patient 2 was diagnosed with recurrent melanoma of the parotid gland with metastatic lesions in the lungs. Patient 2 received stool from Donor 2 and experienced only grade 1 flatus from FMT. At the time of treatment #3, the patient experienced grade 1 constipation. Both patients had a vigorous immune response to FMT measured by changes in the immune subpopulations in peripheral blood one week after FMT, including an increase in CD28+ CD8+ T cells and a decrease in PDL1+ CD3- cells. Following anti-PD1 therapy, both patients had an increase in CD39+ CD8+ T cell population. The PD1+ CD38+ CD8+ dysfunctional T cell levels decreased in both patients post-FMT and anti-PD1 therapy.ConclusionsFMT combined with anti-PD1 therapy in patients with advanced melanoma appears to be safe. A measurable immune response was observed one week after FMT in both patients. One patient experienced several grade 2 toxicities with stabilization of a large cutaneous lesion.AcknowledgementsThis study is funded by a grant from The Lotte & John Hecht Memorial Foundation and a grant from The Medical Oncology Research Funds (MORF) from Western University.Trial RegistrationNCT03772899Ethics ApprovalThe study was approved by Western University Institutution‘s Ethics Board, approval number 113131, date of approval March 15, 2019.

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Sambi, Manpreet, Leila Bagheri et Myron R. Szewczuk. « Current Challenges in Cancer Immunotherapy : Multimodal Approaches to Improve Efficacy and Patient Response Rates ». Journal of Oncology 2019 (28 février 2019) : 1–12. http://dx.doi.org/10.1155/2019/4508794.

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Cancer immunotherapy is a promising innovative treatment for many forms of cancer, particularly melanoma. Although immunotherapy has been shown to be efficacious, patient response rates vary and, more often than not, only a small subset of the patients within a large cohort respond favourably to the treatment. This issue is particularly concerning and becomes a challenge of immunotherapy to improve the effectiveness and patient response rates. Here, we review the specific types of available immunotherapy options, their proposed mechanism(s) of action, and the reasons why the patient response to this treatment is variable. The potential favourable options to improve response rates to immunotherapy will be discussed with an emphasis on adopting a multimodal approach on the novel role that the gut microbiota may play in modulating the efficacy of cancer immunotherapy.

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Ruella, Marco, Mireia Uribe-Herranz, Silvia Beghi, Kalpana Parvathaneni, Nektarios Kostopoulos, Guido Ghilardi, Kimberly Amelsberg et al. « Gut Microbiota Tuning Promotes Tumor-Associated Antigen Cross Presentation and Enhances CAR T Antitumor Effects ». Blood 138, Supplement 1 (5 novembre 2021) : 163. http://dx.doi.org/10.1182/blood-2021-151093.

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Abstract Background: Chimeric Antigen Receptor (CAR) T cell immunotherapy has revolutionized the treatment of B-cell malignancies. However, a significant subset of these patients either fails to respond or eventually relapses. Moreover, in solid cancers, CAR T immunotherapy has had little to no success in the clinic so far. In recent years, several studies have shown the influence of commensal gut microbes on T cell function, in particular in the setting of checkpoint immunotherapy. Our group has recently demonstrated that modulation of the gut microbiota using antibiotics such as oral vancomycin (vanco) can enhance the efficacy of tumor-specific T cells in animal models. In this study, we sought to study the effect of vanco-induced dysbiosis on CART immunotherapy using murine models and clinical correlates. Methods and Results: We used the CD19+ A20 lymphoma and the B16 melanoma (transduced with CD19) murine models. Lymphoma- and melanoma-bearing mice were randomized to received oral vanco or vehicle alone (CTR), or in combination with either control untransduced murine T cells (UTD) or murine CART19 (4-1BB). Oral vanco or vehicle treatments started on the day of A20 cells injection and throughout the duration of the experiment (40-45 days). A20-bearing mice treated with CART19+vanco showed strikingly improved tumor control compared to either vanco alone or UTD+vanco (day 40 tumor volume in mm 3 (mean ± s.e.m): CTR=1,678.8±279.4, UTD=1,803.2±180, UTD+vanco=1,477±174, CART19=1,219±208, CART19+vanco=439.5±122.5 , CART versus CART+vanco Two Way Anova P <0.0001). Of note, CART19+vanco also displayed a longer overall survival as compared to controls (UTD= 0/7 alive at day 45 (0%), UTD+vanco= 2/7 (28.6%), CART19= 4/8 (50%), CART+vanco= 8/8 (100%)). To evaluate whether gut microbiota modulation improves CART therapy against solid tumors, we engrafted mice with CD19+ B16 melanoma cells and treated them with murine CART19 or control T-cells with or without vanco. Mice receiving CART+vanco displayed increased tumor control as compared to CART alone (day 21 tumor volume in mm 3 mean ± s.e.m. CTR=1,820.7±131.3, UTD=1,315.9±360.8, UTD+vanco=1,223.6±297.3, CART=1,315±360.8, CART+vanco=443.8±131.9, Two Way Anova CART versus CART+vanco P <0.0001). To investigate the mechanisms responsible for the improved anti-tumor activity, we analyzed gene-expression (nanoString) of 770 immune-oncology targets in tumor samples collected at day 5 after CART. The Ingenuity analysis showed up-regulation of the cross-presentation pathway in tumors of vanco+CART mice but not in CART alone. The functional validation of this mechanism was performed exploiting the physiological expression in A20 cells of the endogenous ecotropic murine leukemia provirus antigen gp70, also expressed in the colorectal cancer cell line CT26, which, however, lacks CD19 expression. Hence, purified T cells from CART19-treated A20-bearing mice were transferred into mice engrafted with CT26 tumors. These adoptively transferred T cells from CART+vanco group - but not the T cells obtained from mice treated with CART alone - displayed significant anti-tumor activity, (day 19 tumor volume in mm 3 (mean ± s.e.m): CTR= 1,360.6±123.3, CT26+CART= 932.9±234.9, CART+vanco= 402.5±139.4, Two Way Anova CART versus CART+vanco P<0.0044). To validate these data, we generated patient-derived gut microbiota avatars, performing a "human to mouse FMT" and observed increased antigen presentation in avatars treated with CART19+vanco. Lastly, in a cohort of 30 B-cell acute lymphoblastic leukemia patients treated with CART19 (CTL019, NCT02030847), 4 patients exposed to oral vanco in the first 3 weeks after CART infusion showed higher CART19 peak expansion and higher peak cytokine levels (IL6, IL10, IL1Ra) in 3/4 patients exposed to oral vanco compared with matched unexposed patients. Conclusions: These results suggest that the modulation of the gut microbiota using vancomycin affects the outcome of CART therapy in preclinical models with better anti-tumor effect via cross-priming and enhanced CART expansion in tumor samples. In a retrospective cohort of patients with B-ALL receiving vancomycin after CART19 therapy, we observed higher CART expansion and serum inflammatory cytokines. Based on these observations, a clinical trial of oral vanco in patients receiving CD19-directed CAR T cells for B-cell lymphomas is planned. Disclosures Ruella: viTToria biotherapeutics: Research Funding; Tmunity: Patents & Royalties; Novartis: Patents & Royalties; BMS, BAYER, GSK: Consultancy; AbClon: Consultancy, Research Funding. Frey: Novartis: Research Funding; Sana Biotechnology: Consultancy; Kite Pharma: Consultancy; Syndax Pharmaceuticals: Consultancy. June: Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company; AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy; Novartis: Patents & Royalties. Porter: American Society for Transplantation and Cellular Therapy: Honoraria; ASH: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; Genentech: Current Employment, Current equity holder in publicly-traded company; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Unity: Patents & Royalties; Wiley and Sons Publishing: Honoraria. Schuster: TG Theraputics: Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Genentech/Roche: Consultancy, Research Funding; Tessa Theraputics: Consultancy; Loxo Oncology: Consultancy; Juno Theraputics: Consultancy, Research Funding; BeiGene: Consultancy; Alimera Sciences: Consultancy; Acerta Pharma/AstraZeneca: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Abbvie: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Celgene: Consultancy, Honoraria, Research Funding.

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Wang, Liangliang, Hua Laura Liang et Ralph Weichselbaum. « Lactobacillus rhamnosus GG re-shapes gut microbiota and triggers STING-type I IFN-dependent antitumor immunity ». Journal of Immunology 208, n^o 1_Supplement (1 mai 2022) : 120.04. http://dx.doi.org/10.4049/jimmunol.208.supp.120.04.

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Abstract Lactobacillus rhamnosus GG (LGG) is one of the most well characterized and widely used probiotics. The beneficial roles of LGG in modulating immune response and inflammatory state during cancer development have been well demonstrated. However the true therapeutic importance of its role in current radiotherapies and immunotherapies is still unclear. Using murine models of colorectal cancer and melanoma, we demonstrate that oral administration of live LGG augmented the antitumor activity of antiPD-1 immunotherapy and/or radiotherapy in either germ-free mice or specific pathogen-free mice. Whole genome shotgun metagenome sequencing analyses revealed that the combination treatment shifted the gut microbial community towards enrichment in Bacteroidetes, Actinobacteria, Proteobacteria, and Cyanobacteria. Notably, among the enriched species, Lactobacillus murinus and Bacteroides uniformis are known to increase DC activation and CD8+ T cell tumor recruitment. Immunologically, the synergistic antitumor effect of LGG and anti-PD1 relied on the increased tumor-infiltrating dendritic cells (DCs) and cytotoxic CD8+ T cells. Mechanistically, treatment with live LGG triggered cGAS/STING-dependent type I interferon (IFN) production in DCs, which resulted in enhanced cross-priming of tumor-specific CD8+ T cells. In DCs, LGG induced IFN-β production depended on cGAS/STING/TBK1/IRF7 axis, as further evidenced by the transcriptome sequencing. Overall, our results demonstrate that oral administration of LGG mediates antitumor immunity through activating DCs in a cGAS/STING-type I IFN-dependent manner. The study provides an alternative and effective strategy to advance cancer immunotherapies and radiotherapies.

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Lin, Li-Chi, et Yi-Ying Lin. « The Biological Effectiveness and Medical Significance of Far Infrared Radiation (FIR) ». Malaysian Journal of Medical and Biological Research 8, n^o 1 (20 juin 2021) : 41–46. http://dx.doi.org/10.18034/mjmbr.v8i1.564.

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The electromagnetic waves constitute different wavelengths of light from which Far infrared (FIR) is beneficial for living cells. Extensive studies and trials have been conducted over the last two decades in multidimensional biological domains to identify its unlimited health benefits. FIR radiations improve the microcirculation of the human body, stimulate cell growth, penetrate through skin tissues non-invasively, create intramolecular vibrations create an overall healthy metabolism, which ultimately affects overall improved cardiac and metabolic activity. This phenomenon is used to explore different pathological conditions to identify their significance in the medical field. In this review, we explored the biological effectiveness and the medical significance of Far infrared radiation (FIR) in murine melanoma Cell Growth, Lymphedema, airborne viruses, Cardiac diseases, Wound healing and burns, Autonomic Activities, Hemodialysis, Allergic Rhinitis, Aesthetic medicine, textiles, and other domains such as obesity and gut microbiota.

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Pinato, David James, Sarah Howlett, Diego Ottaviani, Heather Urus, Aisha Patel, Takashi Mineo, Cathryn Brock et al. « Antibiotic treatment prior to immune checkpoint inhibitor therapy as a tumor-agnostic predictive correlate of response in routine clinical practice. » Journal of Clinical Oncology 37, n^o 8_suppl (10 mars 2019) : 147. http://dx.doi.org/10.1200/jco.2019.37.8_suppl.147.

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147 Background: Antibiotic therapy (ATB) may impair efficacy of immune checkpoint inhibitors (ICPI) through modulation of gut microbiota. Evidence is however limited to trial participants with non-small cell (NSCLC) and renal cell carcinoma (RCC). In this multi-centre study, we validated the impact of ATB in patients (pts) treated with ICPI in routine practice, irrespective of tumour site. Methods: We analysed a prospective dataset of pts treated with ICPI in 2 centres. We documented timing and duration of ATB administered within 1 month prior to ICPI treatment (pATB) or concurrently (cATB) until ICPI cessation. We evaluated response and overall survival (OS) across ATB+/-. Results: We enrolled 196 pts with NSCLC (n=119), Melanoma (n=38) and other histotypes (n=39). Most pts were male (n=137, 70%) with performance status 0-1 (n=159, 84%) and a median number of 2 metastatic sites (range 0-7). Pts received mostly anti-PD-1/PD-L1 ICPI (n=189, 96%) as first-line metastatic therapy (n=120, 62%). Twenty-nine patients (15%) received pATB with penicillins (n=22, 75%) for ≤7 days (n=26, 89%). Sixty-eight pts (35%) received penicillin-based (n=49, 72%) cATB for ≤7 days (n=39, 88%). Respiratory infections were the commonest indication for both pATB (n=16, 55%) and cATB (n=38, 85%). pATB (p<0.001) but not cATB (p=0.76) was associated with worse OS (26 vs. 2 months, Hazard Ratio 7.4, 95% CI 4.2-12.9) and increased likelihood of primary refractoriness to ICPI (44% vs 81%, p<0.001). pATB consistently worsened OS in NSCLC (26 vs. 2.5 months, p<0.001), melanoma (14 vs 3.9 months, p<0.001) and other tumours (11 vs 1.1 months, p<0.001). In multi-variable analyses pATB (p<0.001, HR 3.4, 95% CI 1.9-6.1) and response to ICPI (p<0.001, HR 8.2, 95% CI 4.0-16.9) predicted for OS independent of histotype, tumour burden, PS. Conclusions: This study suggests pATB to exert an independent detrimental effect on response and survival in unselected pts treated with ICPI in routine clinical practice. Mechanistic studies are urgently required to investigate ATB-mediated alterations of gut microbiota as a determinant of poorer outcome following ICPI treatment.

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Diop, Khoudia, Benlaïfaoui Myriam, Wiam Belkaïd, Alexis Nolin-Lapalme, Julie Malo, Marion Tonneau, Ponce Mayra et al. « Abstract 3524 : Role of the gut microbiota in the development of immune-mediated diarrhea and colitis induced by immune checkpoint inhibitors ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 3524. http://dx.doi.org/10.1158/1538-7445.am2022-3524.

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Abstract The accelerating use of combined immune checkpoint inhibitors (ICI; anti-PD-1 plus anti-CTLA-4 antibodies) enhanced therapeutic responses in various cancers while significantly increasing immune-related adverse events (irAE). The mechanism involved in the occurrence of immune-mediated diarrhea and colitis (IMDC) and its potential implication on ICI efficacy remain unclear. The gut microbiome is progressively recognized as a key biomarker of ICI efficacy and preliminary results suggest its potential association with irAE. However, the link between microbiota and IMDC still needs to be elucidated. In this study, we investigated IMDC-associated intestinal bacteria.We performed metagenomics sequencing of baseline pre-ICI fecal samples from 26 advanced melanoma patients and recorded IMDC. Culturomics using MALDI-TOF was used to isolate bacteria from 19 patient samples: 11 IMDC-free (fIMDC), 5 baseline pre-IMDC (pIMDC) and 8 during IMDC (dIMDC). Serum multiplex cytokine panel was measured for 36 patients. Then, we induced colitis with Dextran Sulfate Sodium (DSS) in MCA-205 murine tumor model treated with oral supplementation of human bacteria and ICI.Metagenomics profiling demonstrated lower α-diversity at baseline in patients that developed irAE. Moreover, pIMDC samples present a lower Simpson α-diversity than fIMDC samples (p=0.08). ß-diversity was also different between both groups (p=0.10) suggesting a different baseline microbiome composition. Lefse analysis revealed an overrepresentation of Enterococcus faecium and Bilophila wadsworthia in pIMDC samples compared to fIMDC samples. Culturomics showed that dIMDC samples exhibited a shift in gut microbiota with a significant decrease in bacterial diversity mostly anaerobic species and an enrichment of Clostridium paraputricum, Clostridium perfringens, Paraclostridium bifermentans and Paeniclostridium sordelii compared to fIMDC and pIMDC samples. Immunological analysis of serum revealed that IMDC patients had a higher concentration of pro-inflammatory cytokines including GMCSF (p=0.04), IL12-23p40 (p=0.04) and IL-16 (p=0.03) compared to fIMDC patients. In our DSS-induced colitis mouse model, we showed that P. bifermentans oral supplementation related with diarrhea and a shorter colon length, indicating more severe colitis. Moreover, we showed that P. bifermentans increased anti-CLTA-4 and anti-PD-1 anti-tumor activity.Results showed that gut microbiota composition of dIMDC patients differed from that of pIMDC and fIMDC patients with a decrease of diversity and colonization of P.bifermentans and P.sordelii. In IMDC patients, we isolated bacteria that aggravated colitis in murine models and are known to be associated with inflammatory bowel disease. These results provide more insight on potential microbiome-modifying strategies to damper IMDC and increase anti-cancer efficacy. Citation Format: Khoudia Diop, Benlaïfaoui Myriam, Wiam Belkaïd, Alexis Nolin-Lapalme, Julie Malo, Marion Tonneau, Ponce Mayra, Afnan Al-Saleh, Catalin Mihalcioiu, Ian Watson, Arielle Elkrief, Karla Lee, Meriem Messaoudene, Bertrand Routy, Corentin Richard. Role of the gut microbiota in the development of immune-mediated diarrhea and colitis induced by immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3524.

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Vanhove, Wiebe, Paul M. Peeters, Isabelle Cleynen, Gert Van Assche, Marc Ferrante, Séverine Vermeire et Ingrid Arijs. « Review Article. Absent in melanoma 2 (AIM2) in the intestine : diverging actions with converging consequences ». Inflammasome 3, n^o 1 (1 janvier 2017) : 1–9. http://dx.doi.org/10.1515/infl-2017-0001.

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AbstractThe intestinal mucosa is a difficult environment to maintain homeostasis as it is constantly challenged by microbial and food antigens. Maintaining an intact epithelial barrier, a continuous turnover of intestinal epithelial cells and normobiosis of the gut microbiota are essential components to prevent intestinal diseases such as inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Inflammasomes are critical immune regulators that are involved in all of these processes. They are multiprotein complexes able to assemble upon interaction with a noxious stimulus that will subsequently lead to caspase-1 activation. Activated caspase-1 will orchestrate the maturation and release of proinflammatory cytokines IL-1β and IL-18, and induce pyroptosis, an inflammatory form of cell death. Both cytokine release and pyroptosis are initiated after detection of molecular patterns by a distinct inflammasome sensor protein. Absent in melanoma 2 (AIM2) is such an inflammasome sensor that specifically responds to the presence of double stranded DNA (dsDNA) in the cytoplasm, leading to the recruitment and activation of caspase-1. Recent studies revealed additional roles of AIM2 in controlling epithelial cell proliferation, tight junction expression and the microbiome. Therefore, AIM2 plays a significant role in maintaining intestinal homeostasis. This review focuses on the multifunctional role of AIM2 in intestinal homeostasis by regulating intestinal immunity and preventing colorectal cancer development.

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Leung, Hoi Kit Matthew, Emily Kwun Kwan Lo et Hani El-Nezami. « Theabrownin Alleviates Colorectal Tumorigenesis in Murine AOM/DSS Model via PI3K/Akt/mTOR Pathway Suppression and Gut Microbiota Modulation ». Antioxidants 11, n^o 9 (30 août 2022) : 1716. http://dx.doi.org/10.3390/antiox11091716.

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Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide, yet therapeutic options for CRC often exhibit strong side effects which cause patients’ well-being to deteriorate. Theabrownin (TB), an antioxidant from Pu-erh tea, has previously been reported to have antitumor effects on non-small-cell lung cancer, osteosarcoma, hepatocellular carcinoma, gliomas, and melanoma. However, the potential antitumor effect of TB on CRC has not previously been investigated in vivo. The present study therefore aimed to investigate the antitumor effect of TB on CRC and the underlying mechanisms. Azoxymethane (AOM)/dextran sodium sulphate (DSS) was used to establish CRC tumorigenesis in a wild type mice model. TB was found to significantly reduce the total tumor count and improve crypt length and fibrosis of the colon when compared to the AOM/DSS group. Immunohistochemistry staining shows that the expression of the proliferation marker, Ki67 was reduced, while cleaved caspase 3 was increased in the TB group. Furthermore, TB significantly reduced phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), and the downstream mechanistic target of rapamycin (mTOR)and cyclin D1 protein expression, which might contribute to cell proliferation suppression and apoptosis enhancement. The 16s rRNA sequencing revealed that TB significantly modulated the gut microbiota composition in AOM/DSS mice. TB increased the abundance of short chain fatty acid as well as SCFA-producing Prevotellaceae and Alloprevotella, and it decreased CRC-related Bacteroidceae and Bacteroides. Taken together, our results suggest that TB could inhibit tumor formation and potentially be a promising candidate for CRC treatment.

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Frankel, Arthur E., Laura A. Coughlin, Jiwoong Kim, Thomas W. Froehlich, Yang Xie, Eugene P. Frenkel et Andrew Y. Koh. « Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients ». Neoplasia 19, n^o 10 (octobre 2017) : 848–55. http://dx.doi.org/10.1016/j.neo.2017.08.004.

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Gajewski, Thomas F. « Abstract PL04-03 : Germline and microbiome variants impact immunotherapy efficacy through modulation of myeloid cells ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : PL04–03—PL04–03. http://dx.doi.org/10.1158/1538-7445.am2022-pl04-03.

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Abstract Most cancers express tumor antigens that can be recognized by T cells of the host. The fact that cancers become clinically relevant and grow nonetheless implies that immune escape must occur to allow cancer outgrowth. We have observed two major phenotypes of human melanoma metastases based on gene expression profiling and confirmatory assays. One subgroup of patients has a T cell-inflamed phenotype that includes expression of chemokines, T cell markers, and a type I IFN signature. In contrast, the other major subset lacks this phenotype and appears to display immune “exclusion”. Factors that influence the degree of spontaneous immune infiltration are being investigated, as sources of inter-patient heterogeneity. These include tumor cell-intrinsic oncogenic events, the composition of the gut microbiota, and polymorphisms in immune regulatory genes. We now know that each of these dimensions can be functionally important. The first tumor cell-intrinsic oncogenic pathway identified that mediates immune exclusion is the Wnt/β-catenin pathway. Tumors with active β-catenin fail to recruit Batf3-lineage dendritic cells into the tumor site. Regarding the commensal microbiota, mouse models identified commensal Bifidobacterium as one key component that augments spontaneous anti-tumor immunity and increases efficacy of anti-PD-L1 therapy in vivo. Similar analyses in human cancer patients revealed bacteria sequences enriched in anti-PD-1 responders, and also bacteria sequences enriched in non-responders. Fecal transfer into germ-free mice has confirmed a causal role for the gut microbiota in regulating immunotherapy efficacy. Recent experiments have revealed that one major mechanism by which gut microbes impact on distant ani-tumor immunity is through modulation of immune-regulatory myeloid cells, ie the M1/M2 ratio and MDSCs. Regarding germline variants, our first identified SNP connected to immune cell infiltration is in the PKCδ gene. Loss of function variants are associated with greater immune cell infiltration. PKCδ knockout hosts show improved immune-mediated tumor control and anti-PD-L1 efficacy, but with comparable T cell priming. However, activated T cell accumulation in the tumor microenvironment increases overtime, which is associated with a shift from M2 to M1. Myeloid cell-specific PKCδKO mice using LysM-Cre Tg mice recapitulate the phenotype. Thus, in each of these 3 instances, tumor and host factors impact on anti-tumor immunity by modulating myeloid cell participation—Batf3-DCs, MDSCs, and M1/M2 cells. Citation Format: Thomas F. Gajewski. Germline and microbiome variants impact immunotherapy efficacy through modulation of myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr PL04-03.

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Gaucher, Louis, Leslie Adda, Alice Séjourné, Camille Joachim, Chaby Guillaume, Claire Poulet, Sophie Liabeuf et al. « Associations between dysbiosis-inducing drugs, overall survival and tumor response in patients treated with immune checkpoint inhibitors ». Therapeutic Advances in Medical Oncology 13 (janvier 2021) : 175883592110005. http://dx.doi.org/10.1177/17588359211000591.

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Background: There are conflicting data on the effects of dysbiosis-inducing drugs, and especially antibiotics (ATBs), on clinical outcomes in patients treated with immune checkpoint inhibitors (ICIs). There is a particular lack of data for patients with melanoma. Methods: We performed a single-center retrospective study of the associations between ATBs and other drugs known to modify the gut microbiota (proton pump inhibitors, nonsteroidal anti-inflammatory drugs, statins, opioids, anti-vitamin K, levothyroxine, vitamin D3, antiarrhythmics, metformin and phloroglucinol), overall survival (OS) and tumor response in consecutive cancer patients (particularly those with melanoma) treated with an ICI (ipilimumab, nivolumab or pembrolizumab) over a 9-year period. Results: A total of 372 patients were included. The mean ± standard deviation age was 64.0 ± 12.1 years. The most frequently prescribed ICI was nivolumab (in 58.3% of patients) and the most frequent indications were lung cancer (44.6%) and melanoma (29.6%). Overall, 112 patients (30.1%) had received ATBs. ATB use was associated with (1) shorter OS in the study population as a whole [adjusted hazard ratio [95% confidence interval (CI)]: 1.38 (1.00–1.90), p = 0.048] and in patients with melanoma [adjusted hazard ratio (95% CI): 2.60 (1.06–6.39), p = 0.037], and (2) a lower response rate in the study population as a whole [8.1%, versus 31.1% in patients not treated with ATBs; adjusted odds ratio (95% CI): 6.06 (2.80–14.53), p < 0.001] and in patients with melanoma [adjusted odds ratio (95% CI): 4.41 (1.04–22.80), p = 0.045]. Sensitivity analyses that minimized the indication bias did not reveal an association between OS and the presence of an infection requiring ATBs (quantified as the severity of infection, hospitalization for an infection, or ICI discontinuation). Other dysbiosis-inducing drugs were not associated with a difference in OS. Conclusion: Unlike other dysbiosis-inducing drugs, ATBs were associated with poorer clinical outcomes in ICI-treated patients overall and in the subset of patients with melanoma.

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Elalaoui, Kenza, Claudia Weihe, Andrew Oliver, Brianna Craver, Hew Yeng Lai, Stefan Brooks, Daniel Kim, Jennifer Martiny, Katrine Whiteson et Angela Fleischman. « Investigating the Role of the Gut Microbiome in the Inflammatory State of Myeloproliferative Neoplasms ». Blood 132, Supplement 1 (29 novembre 2018) : 3051. http://dx.doi.org/10.1182/blood-2018-99-109761.

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Abstract The human microbiome is composed of trillions of micro-organisms living in symbiosis with the human body. The interest in the microbiome and the clinical impact of its disruption (dysbiosis) has grown exponentially in the past years, especially in the oncology field. Microbiota play an instructive role in chronic inflammatory disorders and determine response to checkpoint inhibitors cancers, such as melanoma. Increased inflammation in myeloproliferative neoplasms (MPN) drive many of the symptoms associated with this disease and inflammation also likely plays an important role as a driver of the disease. We hypothesized that the microbiome may be dysregulated in MPN which could contribute to the increased inflammatory cytokines seen in this disease and that the microbiome could also potentially impact symptom burden. We compared the gut microbiota of 25 patients with classical MPN, essential thrombocythemia (ET), polycythemia vera (PV) and primary and secondary myelofibrosis (MF) to that of 25 normal controls. Whenever possible, co-inhabiting adults such as a spouse were used as normal controls. Exclusion criteria were acute illness and antibiotics treatment for three months preceding the study. Each participant collected three stool specimens in the course of one week and a subset of the group (n=20) had peripheral blood drawn. The stool microbiome was analyzed using 16S rRNA sequencing and plasma inflammatory cytokines (TNFα, IL-6, IL-8, IL-17a, IL-10, IFNγ, IFNa2, IL-22, IL1-β, GRO, IP-10) were measured using Luminex multiplex analysis. Participants also completed an intake survey which included symptom burden (MPN-SAF TSS) and dietary intake. Characteristics of our MPN patient cohort and normal controls are shown in Table 1. Plasma levels of TNFα and IP-10 were significantly higher in the MPN group versus normal controls (respectively p=0.013 and p=0.0050). We divided the group into those with high (MPN-SAF > 20) and low (MPN-SAF ≤ 20) symptom burden, 7 (28%) patients had high symptom burden affecting considerably their quality of life. Fatigue and early satiety were the most common complaints. GRO (CXCL1) was significantly lower in MPN patients MPN patients with a lower symptom burden (p=0.0287) as compared to those with a high symptom burden. The 16S rRNA gene sequencing did not reveal a significant difference between MPN patients and their healthy counterparts (PERMANOVA, p = 0.83), a large amount of variance in the microbiome data was explained by the individual (PERMANOVA, p= 0.0001), in concordance with other studies suggesting that the microbiome is highly individualistic. To determine whether certain taxa are differentially represented in MPN patients as compared to normal controls, a SIMPER test was used. Prevotellaceae, a family of bacteria implicated in chronic inflammatory conditions, was 20% higher in MPN patients than in normal controls. To test which cytokines explained the most variance in the microbiome data, a distance-based linear model was used (DistLM). TNFα and IL-17a, taken alone, explain 18.7% and 14.5% respectively. The microbiome of patients with a high symptom burden was not significantly different from MPN patients with low symptom burden. We did find a significant difference between the microbiomes of patients treated with Ruxolitinib versus Hydroxyurea. Taken together, this pilot study suggests that inflammation associated with MPN may be driving changes in the microbiome at a finer level, undetected when comparing broad microbial diversity metrics between health and disease. It is still not clear whether the inflammation first modulates the microbiome or whether the gut microbiota triggers the inflammatory signals driving the disease. A larger number of subjects may help answer these questions. Disclosures No relevant conflicts of interest to declare.

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Wang, Yinghong, Weijie Ma, Hamzah Abu-Sbeih, Zhi-Dong Jiang et Herbert L. DuPont. « Fecal microbiota transplantation (FMT) for immune checkpoint inhibitor induced–colitis (IMC) refractory to immunosuppressive therapy. » Journal of Clinical Oncology 38, n^o 15_suppl (20 mai 2020) : 3067. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3067.

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3067 Background: ICIs are efficacious treatment for several advanced malignancies. IMC can limit their use, and can be refractory to medical treatment (immunosuppression) with significant morbidity. Gut microbiome alteration affects IMC development. We sought FMT as a novel therapy for IMC refractory to immunosuppressive therapy. Methods: 15 patients who received FMT for IMC after failure of immunosuppressive therapy were included (6/2017-1/2020). FMT was performed via colonoscopy with healthy donor’s stool. Results: Median age was 55 years with 67% males. 5 patients received PD(L)-1, one CTLA-4 and 9 on combination. Majority had genitourinary cancers followed by melanoma. Median time from ICI to IMC was 75 days. 14 patients had grade 3-4 diarrhea and 9 had grade 3-4 colitis. Endoscopy showed mucosal inflammation in 12 patients and normal mucosa in 3 patients. IMC was refractory to 2-3 doses of infliximab or vedolizumab after corticosteroids prior to FMT. Median time from IMC onset to FMT was 75 days. 13 patients received one . 11 patients achieved clinical response within 10 days of FMT (7-14). Symptom remission was maintained for a median follow-up of 13 months. 6 patients resumed non ICI cancer treatments after FMT. 4 patients had persistent symptoms; 2 continued on vedolizumab, 1 had total colectomy, and 1 transferred to hospice. 4-8 weeks after FMT, endoscopic remission was achieved in 64% of the 11 patients who responded to FMT. No adverse events were reported. Conclusions: FMT treatment was successful in 73% of patients with for IMC refractory to immunosuppressive therapy. Controlled clinical trials are warranted to confirm our conclusion. [Table: see text]

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Ferrari, Valentina, Alessia Melacarne, Francesca Algieri et Maria Rescigno. « 835 Harnessing the microbiota to increase response rates to immunotherapy ». Journal for ImmunoTherapy of Cancer 9, Suppl 2 (novembre 2021) : A876. http://dx.doi.org/10.1136/jitc-2021-sitc2021.835.

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BackgroundTumor cell clearance by cytotoxic T lymphocytes (CTL) requires expression of relevant antigens on HLA Class I molecules on the surface of tumor cells. Reduced levels of HLA Class I expression is a common method of immune escape, as it hampers tumor-specific CTLs’ ability to detect, recognize, and eliminate tumor cells. Recent data have shown that gut microbiota have a major impact on the clinical response to immune checkpoint inhibitors (ICIs), which could be due to a direct effect on malignant cells. Our hypothesis is that microbiota can influence the immune response by altering HLA Class I expression on tumor cells.MethodsTo investigate the ability of bacteria-based products to upregulate HLA Class I expression, we tested two different proprietary microbial derivatives (MDs) on multiple murine and human tumor primary and immortalized cell lines from various tissues, including: breast, myeloid, melanoma, and colon. We next examined if the change in HLA expression was functional by measuring activation levels and cytotoxic capacity of MART-1-specific CTLs following tumor cell treatment with MDs. Lastly, we administered MDs intra-peritoneally in 4T1-bearing Balb/c mice to sensitize 4T1 tumors to combination treatment with anti-PD-1 ICI.ResultsOur results to date show that in vitro treatment with MDs can upregulate surface HLA, albeit not uniformly across all tumor types, with breast and myeloid tumor cells showing the largest increase across the cell lines tested (figure 1). The MD-dependent HLA increase subsequently boosted CTL recognition of tumor cells without increasing background reactivity. The increased CTL degranulation correlated to the tumor cells’ increased surface HLA expression and was consistent whether the antigen was endogenous (5% increase, p<0.0001, figure 2A) or added exogenously (15%–30% increase, p<0.01 and p<0.0001 figure 2B). In combination with anti-PD-1 in vivo, MD treatment significantly abrogated tumor growth when compared to anti-PD-1 combined with the vehicle control (p<0.0001, figure 3A) and tumors harvested from MD-treated mice expressed higher levels of MHC Class I compared to the vehicle control cohort (p<0.05, figure 3B). Additionally, splenocytes from MD-treated mice showed increased recognition of 4T1 tumor cells when re-challenged in vitro (10% increase in CD8+41BB+ cells, p<0.0001, figure 3C).Abstract 835 Figure 1Class I surface expression after MD treatment. (A) breast (B) colon (C) melanoma and (D) myeloid human cancer cell lines were incubated with 5 (light bars) or 10 (dark bars) mg/mL MD#1, MD#2, and 10 mg/mL respective vehicle control (empty bars). (E) and (F) were treated with 10 mg/mL (dark bars) MD#1, MD#2, or respective vehicle controls (empty bars). After 48 hours, HLA Class I (A-D), H-2kb (E), and H-2kd (F) surface expression was measured by flow cytometry. Experiments repeated at least in duplicate. Statistical analysis by 2-way ANOVA, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.Abstract 835 Figure 2Antigen-specific CTL activation. Tumor cells were pre-treated for 48 hours with 10 mg/mL vehicle or MD, then washed and co-cultured for 5 hours with MART-1 specific CTL. A) primary HLA-A2+ melanoma cells that are negative (Mel12) or positive (Mel13) for the MART-1 antigen, and B) Thp1 loaded or not with MART-1 peptide. CD8+CD107a+ cells measured by flow cytometry. Experiments repeated in triplicate, statistical analysis by two-way ANOVA.Abstract 835 Figure 3In vivo treatment with MD. Fifteen 6-week-old Balb/c mice were subcutaneously inoculated with 1.5 × 1054T1 tumor cells and divided into 3 treatment groups on day 3 based on equivalent tumor size. Mice were treated with 250 µg microbial derivatives (MD#1) or vehicle control (vehicle #1) in combination with anti-PD-1 (200 µg; clone 29F.1A12) starting on day 3 and continued every other day for a total of 4 injections (black arrows). (A) Tumor measurements were taken every other day using a caliper and volume calculated using the formula: tumor volume = (length x width2) ÷ 2 (B) 2 × 105 splenocytes were co-cultured 1:1 with 4T1 tumor cells in vitro and T cell activation (percent CD8+41BB+) was measured by flow cytometry. Experiment repeated in duplicate, statistical analysis by 2-way ANOVA (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001).ConclusionsOur results thus far confirm that our proprietary MDs can increase HLA expression on tumor cells, and that this can lead to increased recognition by antigen-specific CTL both in vitro and in vivo. This suggests that MDs could be explored in combination with ICIs to enhance clinical anti-cancer immune responses.

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Porcari, Serena, Chiara Ciccarese, Federica Pinto, Gianluca Quaranta, Silvia De Giorgi, Debora Rondinella, Carlo Romano Settanni et al. « Fecal microbiota transplantation to improve efficacy of immune checkpoint inhibitors in renal cell carcinoma (TACITO trial). » Journal of Clinical Oncology 40, n^o 6_suppl (20 février 2022) : TPS407. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.tps407.

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TPS407 Background: Renal cell carcinoma (RCC) is the 6° most common cancer in men and the 8° in women in the USA. In Italy RCC incidence was 11,500 new cases in 2017, while mortality was 3,371 cases in 2015. Increasing evidence suggests that response to immune checkpoint inhibitors (ICIs), a novel treatment for advanced RCC (aRCC) and other epithelial tumors, can be influenced by the patient gut microbiota. Fecal microbiota transplantation (FMT) is a novel treatment option aimed to restore healthy gut microbiota, and is the most effective therapy for recurrent C. difficile infection. Preliminary nonrandomized findings show that FMT is able to improve efficacy of ICIs in patients with advanced melanoma. The aim of this study is to evaluate, through a double-blinded placebo-controlled randomized clinical trial, the efficacy of targeted FMT (from donors who are responding to ICIs) in improving response rates to ICIs in subjects with aRCC. Methods: 50 patients who are about to receive, or have started by <8 weeks, pembrolizumab + axitinib as first-line therapy for aRCC will be enrolled. Exclusion criteria include major comorbidities, concomitant GI or autoimmune disorders, or HIV, HBV, HCV infection, continuative corticosteroid therapy, previous treatment with systemic immune-suppressants or immune-modulatory drugs, antibiotic therapy within 4 weeks prior to enrollment. Stool samples and clinical data will be collected at baseline. Then, patients will be randomized to donor FMT or placebo FMT. They will receive the first infusion by colonoscopy and then oral frozen fecal or placebo capsules (8 capsules t.i.d.) 90 and 180 days after the first FMT. Stool donors will be searched among long-term (>12 months) responders to ICIs, and will be selected by following protocols recommended by international guidelines. Patients in the FMT group will always receive feces from the same donor throughout the three fecal transplants. Frozen fecal batches and frozen fecal capsules will be manufactured according to international guidelines. Patients will be followed-up 7, 15, 30, 90, 180, 270, and 360 days after randomization for clinical evaluation and collection of stool samples. Patients will also undergo radiological assessment at 90, 180, 270 and 360 days after randomization. Microbiome analysis will be performed with shotgun metagenomics. The primary endpoint is the progression-free survival (PFS) at 12 months. Secondary endpoints are: objective response rate at 12 months; overall survival at 12 months; adverse events after FMT; microbiome changes after FMT. Sample size calculation was based on the hypothesis that FMT can improve the 1-year PFS rate from 60% (reported 1-year PFS for SOC) to 80% wen associated to SOC. Clinical trial information: NCT04758507.

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Maia, Manuel C., Valeriy Poroyko, Haejung Won, Lorena Almeida, Paulo Gustavo Bergerot, Nazli Dizman, Joann Hsu, Jeremy Jones, Ravi Salgia et Sumanta K. Pal. « Association of microbiome and plasma cytokine dynamics to nivolumab response in metastatic renal cell carcinoma (mRCC). » Journal of Clinical Oncology 36, n^o 6_suppl (20 février 2018) : 656. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.656.

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656 Background: Checkpoint inhibitors (CPI) represent a standard of care in mRCC. The relationship of the microbiome to benefit from CPIs has been suggested in clinical studies in melanoma (Wargo et al ASCO 2017). Here we provide updated evidence of association between microbiome composition, plasma cytokines and response to nivolumab in mRCC patients (pts). Methods: Stool and blood samples were prospectively collected from pts with mRCC at 3 time points relative to nivolumab treatment (baseline, week 4 and week 12) and used to assess gut microbiota composition in two different groups: responders (R; including complete/partial response and stable disease) and non-responders (P; primary progression). For stool analyses, microbial DNA was extracted, 16s rRNA gene tags (v4) were generated by PCR amplification and sequenced using MiSeq (Illumina). Sequence reads were processed by Mothur software, assembled in OTUs, taxonomically annotated and used to construct dissimilarity matrices. Differentially abundant taxa were determined by METASTATS and compared between R and P. We further interrogated whether plasma cytokine profile was influenced by specific bacterial species. Results: Of 20 pts, 16 were evaluable for response. In preliminary analyses, 25,304 OTUs were attributed to 165 genera from 8 phyla. PCoA analysis reveals that the first two principal coordinates can explain 49.2% of data set variation. Subsequent k-means clustering shows an almost complete separation of microbiota in R and P groups (p = 0.07). The analysis of microbiota membership in P and R groups revealed 2 differentially abundant taxonomic units present above 1% abundance. Namely, Roseburia spp and Faecalibacterium spp were significantly elevated in R as compared to P (p < 0.05). Correlations between these bacteria and plasma cytokines will be presented at the meeting. Conclusions: Our results are the first to associate specific microbial genera to nivolumab response in mRCC, and this represents the first effort to combine analysis of the microbiome and serum cytokines. Manipulation of the stool microbiome as a means of modulating nivolumab response should be investigated.

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