Academic literature on the topic 'Tumour-associated macrophages MAT'

BackgroundCancer cells are capable of evading clearance by macrophages through the overexpression of anti-phagocytic, innate immune checkpoint molecules called ‘don’t eat me’ signals, including CD47,1 PD-L1,2 and MHC class I.3 Monoclonal antibodies that antagonize the interaction of ‘don’t eat me’ signals with their macrophage-expressed receptors have demonstrated therapeutic potential in several cancers. However, variability in the magnitude and durability of the responses to these agents has suggested the presence of additional, as yet unknown innate immune checkpoints. Here, we present a functional screening platform which identifies tumor-specific regulators of intratumoral macrophage function. We show that CD24 is a dominant innate immune checkpoint in many solid tumors, including ovarian cancer and breast cancer.4MethodsBy applying our screening method, we uncovered the novel innate immune checkpoint molecule, CD24. To characterize the role of CD24 as a macrophage checkpoint, we leveraged the MCF-7 human xenograft tumor model and the ID8 syngeneic ovarian cancer tumor model. We evaluated the anti-tumor effect of CD24 antagonism through genetic ablation experiments in addition to therapeutic CD24 monoclonal antibody (mAb) blockade. We also utilized primary human immune cells and tumor specimens to assess the effect of CD24 blockade either alone or in combination with additional tumor-targeting antibodies.ResultsWe demonstrate that CD24 promotes immune evasion through its interaction with the inhibitory macrophage receptor Siglec-10. Genetic ablation of either CD24 or Siglec-10, as well as blockade of the CD24–Siglec-10 interaction using monoclonal antibodies, robustly augmented the phagocytosis of all CD24-expressing human tumors that we tested. Therapeutic blockade of CD24 resulted in a macrophage-dependent reduction of tumor growth in vivo and an increase in survival time. The therapeutic efficacy of anti-CD24 mAbs was enhanced when combined with a second anti-tumor antibody. In particular, dual treatment of HER2-positive breast cancers with anti-CD24 mAb and trastuzumab, augmented phagocytosis relative to either treatment alone, even among cancers with inherent trastuzumab resistance (figure 1).Abstract 261 Figure 1Macrophage checkpoints are therapeutic targets. (A) There are four defined innate immune checkpoint signaling axes which exist between macrophages and cancer cells, which all rely on ITIM or ITSM signaling on the cytoplasmic side of the macrophage. (B) Phagocytosis of BT-474 (n = 8 donors) in the presence of anti-CD24 mAb, anti-HER2 mAb or dual treatment, compared with IgG control.ConclusionsThese data reveal CD24 as a highly expressed, anti-phagocytic signal in several cancers, and demonstrate the therapeutic potential for CD24 blockade in cancer immunotherapy, either alone or in combination with existing anticancer treatments. Collectively, this work suggests a new paradigm that innate immune checkpoints are redundant and employed in a tissue-specific and even tumor-specific manner, and makes clear the need to measure the collective expression of these ‘don’t eat me’ signals in order to optimize patient responses to both innate and adaptive immunotherapies.ReferencesMajeti R, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 2009;138: 286–299. Gordon SR, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 2017;545:495–499.Barkal AA, et al. Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nat Immunol 2018;19:76–84.Barkal AA, Brewer RE, Markovic M, Kowarsky MA, Barkal SA, Zaro BW, Krishnan V, Hatakeyama J, Dorigo O, Barkal LJ, Weissman IL. CD24 signaling through macrophage siglec-10 is a new target for cancer immunotherapy. Nature 2019;572:392–396.Ethics ApprovalThe Human Immune Monitoring Center Biobank and the Stanford Tissue Bank all received IRB approval from the Stanford University Administrative Panels on Human Subjects Research and complied with all ethical guidelines for human subjects research to obtain samples from patients with ovarian cancer and breast cancer, and received informed consent from all patients.

AbstractPancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease for which better therapies are urgently needed. Fibroblasts and macrophages are heterogeneous cell populations able to enhance metastasis, but the role of a macrophage-fibroblast crosstalk in regulating their pro-metastatic functions remains poorly understood. Here we deconvolve how macrophages regulate metastasis-associated fibroblast (MAF) heterogeneity in the liver. We identify three functionally distinct MAF populations, among which the generation of pro-metastatic and immunoregulatory myofibroblastic-MAFs (myMAFs) critically depends on macrophages. Mechanistically, myMAFs are induced through a STAT3-dependent mechanism driven by macrophage-derived progranulin and cancer cell-secreted leukaemia inhibitory factor (LIF). In a reciprocal manner, myMAF secreted osteopontin promotes an immunosuppressive macrophage phenotype resulting in the inhibition of cytotoxic T cell functions. Pharmacological blockade of STAT3 or myMAF-specific genetic depletion of STAT3 restores an anti-tumour immune response and reduces metastases. Our findings provide molecular insights into the complex macrophage–fibroblast interactions in tumours and reveal potential targets to inhibit PDAC liver metastasis.

Abstract The unmet clinical need for effective treatments in ovarian cancer has yet to be addressed using monoclonal antibodies (mAbs), which have largely failed to overcome tumour-associated immunosuppression, restrict cancer growth, and significantly improve survival. In recent years, experimental mAb design has moved away from solely targeting ovarian tumours and instead sought to modulate the wider tumour microenvironment (TME). Tumour-associated macrophages (TAMs) may represent an attractive therapeutic target for mAbs in ovarian cancer due to their high abundance and close proximity to tumour cells and their active involvement in facilitating several pro-tumoural processes. Moreover, the expression of several antibody crystallisable fragment (Fc) receptors and broad phenotypic plasticity of TAMs provide opportunities to modulate TAM polarisation using mAbs to promote anti-tumoural phenotypes. In this review, we discuss the role of TAMs in ovarian cancer TME and the emerging strategies to target the contributions of these cells in tumour progression through the rationale design of mAbs.

Abstract Aims/hypothesis Immunomodulators blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have improved the treatment of a broad spectrum of cancers. These immune checkpoint inhibitors (ICIs) reactivate the immune system against tumour cells but can also trigger autoimmune side effects, including type 1 diabetes. Mesenchymal stem cell (MSC) therapy is the most prevalent cell therapy, with tissue-regenerating, anti-fibrosis and immunomodulatory functions provided by the secretome of the cells. Here, we examined whether systemic MSC treatment could prevent the development of type 1 diabetes in a NOD mouse model. Methods The purified PD-L1 monoclonal antibody was administered to induce diabetes in male NOD mice which normally do not develop diabetes. Human adipose-derived MSCs were administered by tail vein injections. T cells, macrophages and monocyte-derived macrophages expressing C-X-C motif chemokine ligand 9 (CXCL9) in pancreatic sections of NOD mice and a cancer patient who developed diabetes following the ICI treatments were analysed by immunofluorescence. Tissue localisation of the injected MSCs, plasma exosome levels and plasma cytokine profiles were also investigated. Results PD-1/PD-L1 blockade induced diabetes in 16 of 25 (64%) NOD mice which received anti-PD-L1 mAb without hMSCs [MSC(−)], whereas MSC administration decreased the incidence to four of 21 (19%) NOD mice which received anti-PD-L1 mAb and hMSCs [MSC(+)]. The PD-1/PD-L1 blockade significantly increased the area of CD3-positive T cells (6.2-fold) and macrophage-2 (Mac-2) antigen (2.5-fold)- and CXCL9 (40.3-fold)-positive macrophages in the islets. MSCs significantly reduced T cell (45%) and CXCL9-positive macrophage (67%) accumulation in the islets and the occurrence of diabetes. The insulin content (1.9-fold) and islet beta cell area (2.7-fold) were also improved by MSCs. T cells and CXCL9-positive macrophages infiltrated into the intricate gaps between the beta cells in the islets by PD-1/PD-L1 blockade. Such immune cell infiltration was largely prevented by MSCs. The most striking difference was observed in the CXCL9-positive macrophages, which normally did not reside in the beta cell region in the islets but abundantly accumulated in this area after PD-1/PD-L1 blockade and were prevented by MSCs. The CXCL9-positive macrophages were also observed in the islets of a cancer patient who developed diabetes following the administration of ICIs but few CXCL9-positive macrophages were observed in a control patient. Mechanistically, the injected MSCs accumulated in the lung but not in the pancreas and strongly increased plasma exosome levels and changed plasma cytokine profiles. Conclusions/interpretation Our results suggest that MSCs can prevent the incidence of diabetes associated with immune checkpoint cancer therapy and may be worth further consideration for new adjuvant cell therapy. Graphical abstract

AbstractBackgroundPredictive biomarkers for oesophageal squamous cell carcinoma (ESCC) immunotherapy are lacking, and immunotherapy resistance remains to be addressed. The role of long noncoding RNA (lncRNA) in ESCC immune escape and immunotherapy resistance remains to be elucidated.MethodsThe tumour‐associated macrophage‐upregulated lncRNAs and the exosomal lncRNAs highly expressed in ESCC immunotherapy nonresponders were identified by lncRNA sequencing and polymerase chain reaction assays. CRISPR‐Cas9 was used to explore the functional roles of the lncRNA. RNA pull‐down, MS2‐tagged RNA affinity purification (MS2‐TRAP) and RNA‐binding protein immunoprecipitation (RIP) were performed to identify lncRNA‐associated proteins and related mechanisms. In vivo, the humanized PBMC (hu‐PBMC) mouse model was established to assess the therapeutic responses of specific lncRNA inhibitors and their combination with programmed cell death protein 1 (PD‐1) monoclonal antibody (mAb). Single‐cell sequencing, flow cytometry, and multiplex fluorescent immunohistochemistry were used to analyze immune cells infiltrating the tumour microenvironment.ResultsWe identified a lncRNA that is involved in tumour immune evasion and immunotherapy resistance. High LINC02096 (RIME) expression in plasma exosomes correlates with a reduced response to PD‐1 mAb treatment and poor prognosis. Mechanistically, RIME binds to mixed lineage leukaemia protein‐1 (MLL1) and prevents ankyrin repeat and SOCS box containing 2 (ASB2)‐mediated MLL1 ubiquitination, improving the stability of MLL1. RIME‐MLL1 increases H3K4me3 levels in the promoter regions of programmed death‐ligand 1 (PD‐L1) and indoleamine 2,3‐dioxygenase 1 (IDO‐1), constitutively increasing the expression of PD‐L1/IDO‐1 in tumour cells and inhibiting CD8+ T cells infiltration and activation. RIME depletion in huPBMC‐NOG mice significantly represses tumour development and improves the effectiveness of PD‐1 mAb treatment by activating T‐cell‐mediated antitumour immunity.ConclusionsThis study reveals that the RIME‐MLL1‐H3K4me3 axis plays a critical role in tumour immunosuppression. Moreover, RIME appears to be a potential prognostic biomarker for immunotherapy and developing drugs that target RIME may be a new therapeutic strategy that overcomes immunotherapy resistance and benefits patients with ESCC.

Summary Mucosa-associated invariant T (MAIT) cells are evolutionarily conserved, innate-like T lymphocytes with enormous immunomodulatory potentials. Due to their strategic localization, their invariant T cell receptor (iTCR) specificity for major histocompatibility complex-related protein 1 (MR1) ligands of commensal and pathogenic bacterial origin, and their sensitivity to infection-elicited cytokines, MAIT cells are best known for their antimicrobial characteristics. However, they are thought to also play important parts in the contexts of cancer, autoimmunity, vaccine-induced immunity, and tissue repair. While cognate MR1 ligands and cytokine cues govern MAIT cell maturation, polarization and peripheral activation, other signal transduction pathways, including those mediated by costimulatory interactions, regulate MAIT cell responses. Activated MAIT cells exhibit cytolytic activities and secrete potent inflammatory cytokines of their own, thus transregulating the biological behaviours of several other cell types, including dendritic cells, macrophages, natural killer cells, conventional T cells and B cells, with significant implications in health and disease. Therefore, an in-depth understanding of how costimulatory pathways control MAIT cell responses may introduce new targets for optimized MR1/MAIT cell-based interventions. Herein, we compare and contrast MAIT cells and mainstream T cells for their expression of classic costimulatory molecules belonging to the immunoglobulin superfamily and the tumour necrosis factor (TNF)/TNF receptor superfamily, based not only on the available literature but also on our transcriptomic analyses. We discuss how these molecules participate in MAIT cells’ development and activities. Finally, we introduce several pressing questions vis-à-vis MAIT cell costimulation and offer new directions for future research in this area.

Malgré un traitement multimodal agressif associant chirurgie, radiothérapie et chimiothérapie, le glioblastome (GBM) récidive systématiquement. Les récidives sont dues, au moins en partie, à la présence de cellules souches de glioblastome (CSG) qui sont résistantes aux traitements et, en particulier, à l'irradiation. En outre, les CSG sont situées dans un microenvironnement tumoral favorisant leur développement. Notamment, les CSG sont associées aux vaisseaux qui régulent leur prolifération, leur survie et favorisent leur invasion. Par ailleurs, les macrophages associés aux tumeurs (MAT) représentent la population la plus abondante des cellules non tumorales au sein des GBM et leur abondance est corrélée à la gravité des GBM. Ces TAM proviennent du recrutement de monocytes circulants et des cellules microgliales (macrophages résidents) qui acquièrent des propriétés immunosuppressives (pro-tumorales). Le développement récent d'organoïdes cérébraux humains obtenus à partir de cellules souches pluripotentes induites humaines (IPSC) permet de modéliser la physiologie et la physiopathologie du cerveau tel que le gliome. Ces organoïdes sont des structures 3D avatars du cerveau et issus de la différenciation de cellules souches embryonnaires ou d'IPSC. Cependant, la plupart des modèles d'organoïdes sont dépourvus de systèmes vasculaire et immunitaire qui jouent un rôle essentiel dans le cerveau sain et dans les mécanismes physiopathologiques. L'objectif de ma thèse a été de développer un nouveau modèle d'organoïdes cérébraux complexes contenant une vascularisation et des cellules immunitaires afin de modéliser le microenvironnement tumoral du GBM. Plusieurs lignées humaines d'IPSC ont été différenciées pour obtenir d'une part des organoïdes cérébraux et d'autre part des hémangioblastes (progéniteurs bipotents hématopoïétiques /endothéliaux). L'incorporation d'hémangioblastes dans les organoïdes cérébraux a été réalisée précocement au cours de leur formation afin de mimer la colonisation du cerveau, au cours du développement cérébral, par les cellules endothéliales et les macrophages primitifs qui sont à l'origine des vaisseaux et des cellules microgliales. Ces organoïdes cérébraux complexes ont été caractérisés par différentes approches d'immunohistologie, FACS et RT-qPCR. De vastes structures vasculaires se sont développées dans les organoïdes et présentaient des caractéristiques de la barrière hématoencéphalique. De plus, ces structures vasculaires étaient perfusées lorsque les organoïdes ont été transplantés dans des souris immunodéficientes. Des cellules présentant un phénotype ainsi que des fonctionnalités caractéristiques des cellules microgliales se sont également développées dans les organoïdes complexes. Des lignées de CSG, dérivées de patients atteints de GBM ou d'astrocytome de grade IV, ont été co-cultivées dans les organoïdes complexes puis irradiés, ou non, afin de mimer la radiothérapie. J'ai montré que les CSG semblaient coopter les structures vasculaires et perturbaient l'expression d'une protéine d'adhésion cellulaire dans les cellules endothéliales. Par ailleurs, la présence de CSG dans les organoïdes complexes provoquait une reprogrammation des cellules microgliales en TAM immunosuppresseurs. Enfin, les CSG avaient une capacité de prolifération accrue après irradiation et présentaient un profil transcriptomique plus agressif. L'ensemble de ces résultats montre que ces organoïdes cérébraux complexes humains permettent de modéliser un microenvironnement tumoral du GBM ainsi que la récurrence après radiothérapie. En conclusion, notre modèle d'organoïdes cérébraux complexes vascularisés et immunocompétents devrait être utile pour comprendre les mécanismes physiopathologiques de diverses maladies du cerveau comme le GBM et permettra de découvrir de nouvelles thérapies
Despite an aggressive multimodal treatment combining surgery, radiotherapy and chemotherapy, glioblastoma (GBM) systematically recurs. Recurrence is due, at least, to the presence of glioblastoma stem cells (GSC) that are resistant to treatment and, in particular, to irradiation. In addition, GSC are located in a tumour microenvironment that favours their development. Specifically, GSC are associated with vessels, which regulate their proliferation and survival and encourage their invasion. Furthermore, tumour-associated macrophages (TAM) represent the most abundant population of non-tumour cells within GBM and their abundance correlates with GBM severity. These TAM originate from the recruitment of circulating monocytes and microglial cells (resident macrophages) which acquire immunosuppressive (pro-tumour) properties. The recent development of human cerebral organoids obtained from human induced pluripotent stem cells (IPSCs) makes it possible to model the physiology and pathophysiology of the brain, such as gliomas. These organoids are 3D avatars of the brain, derived from the differentiation of embryonic stem cells or induced pluripotent stem cells (IPSC). However, most organoid models lack the vascular and immune systems that play an essential role in the healthy brain and in pathophysiological mechanisms. The aim of my thesis was to develop a new model of complex cerebral organoids containing vascularisation and immune cells in order to model the tumour microenvironment of GBM. Several human IPSC lines were differentiated to obtain both cerebral organoids and hemangioblasts (bipotent hematopoietic/endothelial progenitors). The incorporation of hemangioblasts into the cerebral organoids was carried out early in their formation to mimic the colonisation of the brain, during cerebral development, by endothelial cells and primitive macrophages that are at the origin of vessels and microglial cells. These complex cerebral organoids were characterised using various approaches (immunohistological, FACS and RT-qPCR). Extensive vascular structures developed in the organoids and showed characteristics of the blood-brain barrier. In addition, these vascular structures were perfused when the organoids were transplanted into immunodeficient mice. Cells with a microglial phenotype and typical functionalities also developed in complex organoids. GSC lines derived from patients with GBM or grade IV astrocytoma were co-cultured in complex organoids and then irradiated, or not, to model radiotherapy. I showed that GSC appeared to co-opt vascular structures and disrupted the expression of a cell adhesion protein in endothelial cells. Furthermore, the presence of GSC in complex organoids induced reprogramming of microglial cells into immunosuppressive TAM. Finally, GSC had an increased proliferation capacity after irradiation and presented a more aggressive transcriptomic profile. Taken together, these results show that these complex human cerebral organoids can be used to model GBM tumour microenvironment and recurrence after radiotherapy. In conclusion, our model of complex vascularized and immunocompetent cerebral organoids should be useful for understanding the pathophysiological mechanisms of various brain diseases, such as GBM, and to discover new therapies

Oral, small-molecule signalling pathway inhibitors, including ones that inhibit the JAK and SyK pathways, are currently in development for the treatment of rheumatoid arthritis (RA). Tofacitinib is an orally administered small-molecule inhibitor that targets the intracellular Janus kinase 3 and 1 (JAK1/3) molecules to a greater extent than JAK2 while baricitinib (formerly INCB028050) predominantly inhibits JAK1/2. Many of the proinflammatory cytokines implicated in the pathogenesis of RA utilize cell signalling that involves the JAK-STAT pathways and therefore inhibition of JAK-STAT signalling, by targeting multiple RA-associated cytokine pathways, has the potential to simultaneously reduce inflammation, cellular activation, and proliferation of key immune cells. Fostamatinib disodium is an orally available inhibitor of spleen tyrosine kinase (SyK), which is a cytoplasmic tyrosine kinase that is an important mediator of immunoreceptor signalling in mast cells, macrophages, neutrophils, and B cells. Interruption of SyK signalling may interrupt production of tumour necrosis factor (TNF) and metalloproteinase and therefore affect RA disease activity. Tofacitinib has been investigated in multiple phase 2 and phase 3 trials which have investigated its efficacy (clinical, functional, and radiographic) and safety in patients who have failed disease-modifying anti-inflammatory drugs (DMARDs) as monotherapy or in combination with DMARDs, compared to an inhibitor of tumour necrosis factor alpha (TNFα‎) and in patients who have failed TNFα‎ inhibitors. The efficacy of fostamatinib and baricitinib has been investigated in phase 2 trials; both are in large phase 3 clinical programmes. Each of these medications has demonstrated efficacy; their safety profile has been shown to be different from each other and from currently approved biological agents. This chapter discusses what is currently known and understood about their efficacy and safety.

Oral, small-molecule signalling pathway inhibitors, including ones that inhibit the JAK and other pathways, are currently in development for the treatment of rheumatoid arthritis (RA). Many of the pro-inflammatory cytokines implicated in the pathogenesis of RA utilize cell signalling that involves the JAK-STAT pathways and therefore inhibition of JAK-STAT signalling, by targeting multiple RA-associated cytokine pathways, has the potential to simultaneously reduce inflammation, cellular activation, and proliferation of key immune cells. Spleen tyrosine kinase (SyK) is a cytoplasmic tyrosine kinase that is an important mediator of immunoreceptor signalling in mast cells, macrophages, neutrophils, and B cells. Interruption of SyK signalling should interrupt production of tumour necrosis factor (TNF) and metalloproteinase and therefore affect RA disease activity. Tofacitinib, approved in many countries for the treatment of RA, is an orally administered small-molecule inhibitor that targets the intracellular Janus kinase 3 and 1 (JAK1/3) molecules to a greater extent than JAK2; there are other JAK inhibitors in development which are purported to be more specific for JAK3 (Vertex 509), specific for JAK1/2 (baricitinib) or more specific for JAK1 (Galapagos and INCYTE) where clinical data has been reported. Tofacitinib has been investigated in multiple clinical trials which have investigated its efficacy (clinical, functional, and radiographic) and safety in patients who have failed disease-modifying anti-inflammatory drugs (DMARDs) as monotherapy or in combination with DMARDs, compared to an inhibitor of tumour necrosis factor alpha (TNFα‎‎) and in patients who have failed TNFα‎‎ inhibitors. Vertex 509 has been investigated as monotherapy or in combination with MTX in DMARD failures while baricitinib, GLPG0634 (Galapagos), and INCB039110 (Incyte) have been investigated in phase 1 and 2 clinical trials in combination with MTX. Each of these medications has demonstrated efficacy; their safety profile has been shown to be generally similar although with some differences from each other and some differences from most of the currently approved biological agents. Fostamatinib disodium is an orally available inhibitor of SyK which was investigated in multiple phase 3 clinical trials in RA but was found to be generally ineffective with significant safety signals. This chapter discusses what is currently known and understood about the efficacy and safety of these oral, small-molecule DMARDs.