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Published: 24 May 2023

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1

Grimsley, C. "Cues for apoptotic cell engulfment: eat-me, don't eat-me and come-get-me signals." Trends in Cell Biology 13, no. 12 (December 2003): 648–56. http://dx.doi.org/10.1016/j.tcb.2003.10.004.

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2

Bradley, Conor A. "CD24 — a novel ‘don’t eat me’ signal." Nature Reviews Cancer 19, no. 10 (August 12, 2019): 541. http://dx.doi.org/10.1038/s41568-019-0193-x.

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3

Bradley, Conor A. "CD24 — a novel ‘don’t eat me’ signal." Nature Reviews Drug Discovery 18, no. 10 (August 21, 2019): 747. http://dx.doi.org/10.1038/d41573-019-00146-0.

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4

Majeti, R., C. Jamieson, W. W. Pang, S. Jaiswal, N. J. Leeper, G. Wernig, and I. L. Weissman. "Clonal Expansion of Stem/Progenitor Cells in Cancer, Fibrotic Diseases, and Atherosclerosis, and CD47 Protection of Pathogenic Cells." Annual Review of Medicine 73, no. 1 (January 27, 2022): 307–20. http://dx.doi.org/10.1146/annurev-med-042420-104436.

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We proposed and demonstrated that myelogenous leukemia has a preleukemic phase. In the premalignant phase, normal hematopoietic stem cells (HSCs) gradually accumulate mutations leading to HSC clonal expansion, resulting in the emergence of leukemic stem cells (LSCs). Here, we show that preleukemic HSCs are the basis of clonal hematopoiesis, as well as late-onset blood diseases (chronic-phase chronic myeloid leukemia, myeloproliferative neoplasms, and myelodysplastic disease). The clones at some point each trigger surface expression of “eat me” signals for macrophages, and in the clones and their LSC progeny, this is countered by upregulation of “don't eat me” signals for macrophages such as CD47,opening the possibility of CD47-based therapies. We include evidence that similar processes result in fibroblast expansion in a variety of fibrotic diseases, and arterial smooth muscle clonal expansion is a basis of atherosclerosis, including upregulation of both “eat me” and “don't eat me” molecules on the pathogenic cells.
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Brightwell, R. M., K. S. Grzankowski, S. Lele, K. Eng, M. Arshad, H. Chen, and K. Odunsi. "The CD47 “don't eat me signal” is highly expressed in human ovarian cancer." Gynecologic Oncology 143, no. 2 (November 2016): 393–97. http://dx.doi.org/10.1016/j.ygyno.2016.08.325.

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6

Feng, Mingye, James Y. Chen, Rachel Weissman-Tsukamoto, Jens-Peter Volkmer, Po Yi Ho, Kelly M. McKenna, Samuel Cheshier, et al. "Macrophages eat cancer cells using their own calreticulin as a guide: Roles of TLR and Btk." Proceedings of the National Academy of Sciences 112, no. 7 (February 2, 2015): 2145–50. http://dx.doi.org/10.1073/pnas.1424907112.

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Macrophage-mediated programmed cell removal (PrCR) is an important mechanism of eliminating diseased and damaged cells before programmed cell death. The induction of PrCR by eat-me signals on tumor cells is countered by don’t-eat-me signals such as CD47, which binds macrophage signal-regulatory protein α to inhibit phagocytosis. Blockade of CD47 on tumor cells leads to phagocytosis by macrophages. Here we demonstrate that the activation of Toll-like receptor (TLR) signaling pathways in macrophages synergizes with blocking CD47 on tumor cells to enhance PrCR. Bruton’s tyrosine kinase (Btk) mediates TLR signaling in macrophages. Calreticulin, previously shown to be an eat-me signal on cancer cells, is activated in macrophages for secretion and cell-surface exposure by TLR and Btk to target cancer cells for phagocytosis, even if the cancer cells themselves do not express calreticulin.
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7

Nisha, Sosale, and Dennis E. Discher. "How Does CD47-SIRPα ‘Don’t Eat Me Signal’ Physically Signal Self." Blood 122, no. 21 (November 15, 2013): 953. http://dx.doi.org/10.1182/blood.v122.21.953.953.

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Abstract Resident macrophages in spleen and liver are particularly adept at recognizing foreign pathogens through recognition of ‘non-self’ proteins on the pathogen surface but also through the absence of ‘self’ proteins that are highly displayed on circulating blood cells. Red blood cells display a ‘marker of self’ protein CD47 which increases the in vivo half-life and decreases red-pulp splenic macrophage uptake of mouse RBC (Oldenborg et al, Science 2000) and also of particles displaying human-CD47 in recent studies by our group (Rodriguez et al, Science 2013). CD47 signals self through its counter receptor SIRPa, which is highly expressed on the surfaces of myeloid cells but also highly polymorphic. The CD47 protein functions in vitro as a marker of self toward human SIRPa on human macrophages and monocytes, inhibiting accumulation of myosin II motor protein to the phagocytic synapse (Tsai 2008). The work here aims to clarify when and how CD47-SIRPa inhibition physically signals ‘self’ during macrophage phagocytosis uptake. While it is clear that CD47 reduces the number of uptake events, here we use time-lapse and confocal microscopy to examine the forces of distortion imparted by phagocytes on opsonized red blood cell targets during uptake. Glutaraldehyde-fixed RBC are also used as a model to assess the affects of cell rigidity in this self-recognition process, since rigidity is relevant to processes as diverse as RBC aging and sickle RBC to malaria but also because adhesion (by macrophages) is expected to activate the myosin-II contractility system and oppose CD47 signaling. Through blocking and pharmacological approaches, we parse the pathways between foreign, self, and rigidity sensing. Disclosures: No relevant conflicts of interest to declare.
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8

Pinho, Sandra, Wei Qiaozhi, Maria Maryanovich, Halley Pierce, Fumio Nakahara, and Paul S. Frenette. "Vcam1 Is a "Don't-Eat-Me" Signal on Healthy Hematopoietic and Leukemic Stem Cells." Blood 128, no. 22 (December 2, 2016): 565. http://dx.doi.org/10.1182/blood.v128.22.565.565.

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Abstract Hematopoietic stem cells (HSCs) possess the ability to maintain the entire population of blood cells throughout life and to replenish the hematopoietic system after transplantation into marrow-ablated recipients. In mammalian adults, HSCs predominantly reside in the bone marrow to generate and maintain all blood cell types. HSCs, however, retain their ability to migrate to ectopic niches via the bloodstream, and traffic back to the bone marrow microenvironment via in part the interactions of alpha4 integrins with Vascular Cell Adhesion Molecule-1 (Vcam1, also known as CD106), constitutively expressed by endothelial and stromal cells. In the course of studies to investigate the role of Vcam1 in the macrophage erythroblastic niche, we have found using Vcam1-floxed mice crossed with a Csf1r-iCre (hereafter Vcam1Δ/Δ) that Vcam1 and Cre, using this transgenic line, were expressed on Lineage− (Lin−) c-Kit+ Sca1+ CD48− CD150+ HSCs. Although Vcam1Δ/Δ mice show no significant steady-state hematopoietic defect, transplantation of Vcam1Δ/Δ bone marrow, both in competitive and non-competitive settings, failed to engraft irradiated wild-type recipients. Indeed, ~80% of animals transplanted with Vcam1Δ/Δcells died, and the few that survived failed to successfully engraft secondary recipient mice. Vcam1Δ/Δ HSC/progenitors homed to bone marrow as well as wild-type counterparts and showed no detectable change in apoptosis in the bone marrow. However, syngeneic Vcam1Δ/Δ HSC/progenitors were selectively cleared in vivo by bone marrow macrophages over 4 days. The in vivo Vcam1Δ/Δ HSC/progenitor clearance did not require irradiation-induced damage since in steady-state parabiosis (Vcam1Δ/Δ and wild-type co-joined pairs), Vcam1Δ/Δ HSCs did not engraft the partner after G-CSF-induced mobilization whereas wild-type HSCs engrafted the parabiont partner. In addition, in vitro incubation of bone marrow-derived macrophages with Lin− cells revealed rapid phagocytosis by macrophages of Vcam1Δ/Δ, but not wild-type, cells and phagocytosis was also induced when the integrin alpha4 beta1 (also known as VLA-4) was blocked in wild-type Lin− cells. Thus, these results suggest that Vcam1 expressed on HSCs serves as a novel don't-eat-me signal, controlling the migration in the bone marrow by a macrophage-enabled checkpoint. Since we found that Vcam1 is expressed at higher levels on acute myelogenous leukemia (AML) cells than on healthy HSCs, and high VCAM1 expression correlates with poor prognosis in human AML patients (Ley et. al. NEJM 2013), we examined whether Vcam1 expression by AML cell could affect leukemogenesis in vivo. To test this idea, we generated AML-Vcam1Δ/Δand AML-Control cells by transduction of bone marrow Lin− c-Kit+ Sca1+ cells with the pMSCV-MLL-AF9-GFP oncogene. Strikingly, FACS analysis of primary AML recipient bone marrow revealed a marked reduction (>99%) in the number and percentage of phenotypic Lin− IL7Rα− Sca1− MLL-AF9 GFP+ c-Kithigh CD34low FcγRII/IIIhigh leukemic stem cells in AML-Vcam1Δ/Δmice compared to control. These results were confirmed by imaging analyses, which showed a marked reduction in leukemic infiltration in AML-Vcam1Δ/Δmice compared to control. Kaplan-Meier survival analysis of secondary recipient mice receiving 20,000 GFP+ leukemic cells revealed a significantly greater survival of mice harboring AML-Vcam1Δ/Δ cells relative to AML-Control (P<0.0001). To assess in a pre-clinical experimental setting whether Vcam1 inhibition can alter the course of AML, we established AML in immunocompetent C57BL/6 recipients and started therapy of moribund leukemic mice (>50% circulating AML-GFP+ cells) with a daily injection of saline, IgG control, anti-Vcam1 blocking antibody (100 μg/day), cytarabine (100 mg/kg), or a combination of anti-Vcam1/cytarabine for 5 days. Remarkably, this short treatment with anti-Vcam1 blocking antibody was able to preferentially and significantly reduce the frequency and absolute number of phenotypic bone marrow leukemic stem cells in vivo. In addition, our results suggest that using a blocking anti-Vcam1 antibody synergizes with cytarabine treatment to decrease leukemic burden in vivo. These studies lay the groundwork for the development of a new therapeutic strategy for eliminating leukemia stem cells by modulating the innate immune response. Disclosures Frenette: GSK: Research Funding; Pfizer: Consultancy; PHD Biosciences: Research Funding.
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9

Rivest, Serge. "A ‘don’t eat me’ immune signal protects neuronal connections." Nature 563, no. 7729 (October 29, 2018): 42–43. http://dx.doi.org/10.1038/d41586-018-07165-8.

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10

Russ, Atlantis, Anh B. Hua, William R. Montfort, Bushra Rahman, Irbaz Bin Riaz, Muhammad Umar Khalid, Jennifer S. Carew, Steffan T. Nawrocki, Daniel Persky, and Faiz Anwer. "Blocking “don't eat me” signal of CD47-SIRPα in hematological malignancies, an in-depth review." Blood Reviews 32, no. 6 (November 2018): 480–89. http://dx.doi.org/10.1016/j.blre.2018.04.005.

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11

Wedekind, Silke. "Refraktäre Lymphome: Neuer Antikörper überwindet das „Don’t-eat-me-Signal“." InFo Hämatologie + Onkologie 22, no. 9 (September 2019): 63. http://dx.doi.org/10.1007/s15004-019-6670-2.

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12

Sun, Jennifer, Barbara Muz, Kinan Alhallak, Matea Markovic, Shannon Gurley, Zhe Wang, Nicole Guenthner, et al. "Targeting CD47 as a Novel Immunotherapy for Multiple Myeloma." Cancers 12, no. 2 (January 28, 2020): 305. http://dx.doi.org/10.3390/cancers12020305.

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Multiple myeloma (MM) remains to be incurable despite recent therapeutic advances. CD47, an immune checkpoint known as the “don’t eat me” signal, is highly expressed on the surface of various cancers, allowing cancer cells to send inhibitory signals to macrophages and impede phagocytosis and immune response. In this study, we hypothesized that blocking the “don’t eat me” signaling using an anti-CD47 monoclonal antibody will induce killing of MM cells. We report that CD47 expression was directly correlated with stage of the disease, from normal to MGUS to MM. Moreover, MM cells had remarkably higher CD47 expression than other cell populations in the bone marrow. These findings indicate that CD47 is specifically expressed on MM and can be used as a potential therapeutic target. Further, blocking of CD47 using an anti-CD47 antibody induced immediate activation of macrophages, which resulted in induction of phagocytosis and killing of MM cells in the 3D-tissue engineered bone marrow model, as early as 4 hours. These results suggest that macrophage checkpoint immunotherapy by blocking the CD47 “don’t eat me” signal is a novel and promising strategy for the treatment of MM, providing a basis for additional studies to validate these effects in vivo and in patients.
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13

Mohanty, Suchismita, Maryam Aghighi, Ketan Yerneni, Johanna Lena Theruvath, and Heike E. Daldrup‐Link. "Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell ‘don't eat me’ signals off and ‘eat me’ signals on." Molecular Oncology 13, no. 10 (August 13, 2019): 2049–61. http://dx.doi.org/10.1002/1878-0261.12556.

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14

Suresh, Madheswaran, Malarvizhi Gurusamy, and Natarajan Sudhakar. "MASKING ANTI-PHAGOCYTIC SIGNAL OF TUMOR BY PRO-PHAGOCYTIC SIGNAL-A KEY TO IMMUREMENT OF CANCER CELL." International Journal of Pharmacy and Pharmaceutical Sciences 8, no. 9 (September 1, 2016): 323. http://dx.doi.org/10.22159/ijpps.2016v8i9.12990.

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<p>Immune surveillance is a mechanism where cells and tissues are watched constantly by ever alerted immune system. Most incipient cancer cells are recognized and eliminated by the immune surveillance mechanism, but still tumors have the ability to evade immune surveillance and immunological killing. One greater arm that tumor use to evade immune surveillance, is by expressing anti-phagocytic signal (CD47). Here we present a provocative hypothesis where cancer cells are removed alive by phagocytic cell (DC). That in turn will elicit effective and higher immunogenic condition. All this could be possible by addition pro-phagocytic signal (PtdSer) over cancer cell surface (Breast Cancer), that mask the presence of anti-phagocytic signal (CD47). In other words, adding eat me signal (PtdSer) over the breast cancer cell surface that mask the presence of don’t eat me signal or anti-phagocytic signal present in breast cancer cell surface. This could be possible by using bi-specific antibody, conjugated to PEG-modified liposomes, which carry (PtdSer) pro-phagocytic signal (or) eat me signal, which target both CD47 and EGFRVIII on breast carcinoma. The simultaneous masking of anti-phagocytic signal, and adding of pro–phagocytic signal over cancer cell, will enhance the phagocytic clearance of live tumor cell and elicit immunological killing.</p>
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15

Aroldi, Andrea, Mario Mauri, Matteo Parma, Elisabetta Terruzzi, Marilena Fedele, Paola Perfetti, Federica Cocito, et al. "CD24/Siglec-10 "Don't Eat Me" Signal Blockade Is a Potential Immunotherapeutic Target in Mantle-Cell Lymphoma." Blood 138, Supplement 1 (November 5, 2021): 2276. http://dx.doi.org/10.1182/blood-2021-154086.

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Abstract Introduction Mantle-cell lymphoma (MCL) is a B-cell non-Hodgkin Lymphoma (NHL) characterized by heterogenous behavior, ranging from indolent phenotype to highly aggressive and drug resistant one with dismal prognosis. Drug resistance may be generated by Tumor Microenvironment (TME), owing that Tumor-Associated Macrophages (TAM) are pathologically functional in providing survival signals to MCL cells (Pham, Front Oncol. 2018). Recently, "Don't Eat Me" signal (DEMs) blockade with anti-CD47 monoclonal Antibody (moAb) showed promising activity in pretreated NHL, through increase of phagocytosis by TAM (Advani, NEJM. 2019). CD24 was also demonstrated to be involved in DEMs and, in a preclinical model of solid cancer, blocking the CD24/Siglec-10 interaction provided an improvement of M2-like TAM-mediated phagocytosis in vitro and an increase of survival in vivo (Barkal, Nature. 2019). CD24 can be expressed in some phases of B-cell differentiation and MCL derives from a B-cell precursor with upregulated CD24. To date, there are no functional studies showing an improvement of phagocytosis through CD24/Siglec-10 pathway inhibition in hematologic malignancies and MCL. Here, we present our in vitro results of CD24/Siglec-10 DEMs blockade in MCL subset. Methods A panel of MCL cell lines (Jeko-1, Granta-519, Mino) has been analyzed for CD24 surface expression by flow cytometry (FC) (clone SN3). Consequently, we performed co-culture experiments with MCL cell lines and macrophages from healthy donors. Briefly, Peripheral Blood Mononucleated Cells (PBMC) were collected from healthy volunteers through density gradient centrifugation technique. CD14+ monocytes were isolated through CD14 Microbeads isolation kit and cultured in plates with 50 ng/ml human GM-CSF for 7-9 days. In order to create M2-like Siglec-10+ TAM, 50 ng/ml human IL-10 and 50 ng/ml human TGF-β 1 were added on days 3-4 of differentiation until use on days 7-9. Siglec-10 expression on TAM was checked by FC (clone 5G6). M2-like macrophages were then collected and co-cultured with CFSE-labelled MCL target cells for 1-2 hours in a serum-free medium. Anti-CD24 moAb (clone SN3) or the appropriate IgG 1 isotype control were added at a concentration of 10 μg/ml. Phagocytosis was then stopped on ice and CD11b-PE staining (anti-CD11b moAb, clone REA713) was performed to identify human macrophages by FC. Phagocytosis was measured as the number of CD11b+/CFSE+ macrophages, quantified as a percentage of the total CD11b+ macrophages. Each phagocytosis reaction was performed in technical triplicate and phagocytosis was normalized to the highest technical replicate per donor in order to consider raw phagocytic level among donor-derived macrophages. Results MCL cell lines express surface CD24 by FC, with higher levels in Mino cell line (Figure 1A). Differentiated M2-like macrophages showed an upregulation of Siglec-10 expression after immunosuppressive stimuli, which is fundamental owing that Siglec-10 is the ligand of CD24 (Figure 1B). As pertains to the phagocytic assay, we documented an improvement of phagocytosis when M2-like macrophages and MCL cell lines were co-cultured together with anti-CD24 moAb (Figure 2 and Figure 3A). Furthermore, it is worth mentioning that phagocytosis seemed to be much higher in MCL cell lines with higher surface levels of CD24 (e.g., Mino), presenting increased number of CD11b+/CFSE+ M2-like TAM by FC (Figure 3B). Conclusions MCL was found to be sensitive to CD24/Siglec-10 DEMs blockade when co-cultured with M2-like macrophages in vitro. We can argue that most of the observed increase of phagocytosis after the addition of anti-CD24 moAb may be secondary to loss of CD24 signalling rather than Fc-mediated opsonization, as already documented in previous analysis about solid cancer (Barkal, Nature. 2019). We can therefore hypothesize that the blockade of this DEMs pathway can improve phagocytosis in a non-opsonization manner in NHL as well. Furthermore, CD24 surface density seemed to be positively correlated to the intensity of phagocytic activity, suggesting that MCL subtypes expressing higher CD24 levels are much more dependent on this DEMs pathway than others with low CD24 density. Overall, CD24 turned out to be a potential immunotherapeutic target in MCL, aiming at improving innate immune system through DEMs blockade. In vivo studies are needed to confirm the activity we documented in vitro in this NHL subset. Figure 1 Figure 1. Disclosures Gambacorti-Passerini: Bristol-Myers Squibb: Consultancy; Pfizer: Honoraria, Research Funding.
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16

Klausz, Katja, Carina Lynn Gehlert, Ammelie Svea Boje, Marta Lustig, Steffen Krohn, Syeda Maliha Ahmed, Christian Kellner, et al. "Blocking the Don't Eat Me Signal (CD47-SIRPα Axis) to Improve Antibody-Based Immunotherapy of Multiple Myeloma." Blood 138, Supplement 1 (November 5, 2021): 2684. http://dx.doi.org/10.1182/blood-2021-152208.

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Abstract The addition of monoclonal antibodies daratumumab, elotuzumab and isatuximab to the treatment of patients with multiple myeloma significantly improved the outcome and prolonged survival. Unfortunately, although many patients benefit, depth and duration of response are a problem. In order to improve efficacy of antibody-based immunotherapy, we aimed to combine CD38-directed antibodies daratumumab and isatuximab as well as SLAMF7-targeting elotuzumab with a CD47 blocking antibody to enhance phagocytosis of myeloma cells. Antibody-dependent cellular phagocytosis (ADCP) of malignant plasma cells is described to be one important mode of action of daratumumab, isatuximab and elotuzumab, respectively. Of note, CD47 is highly expressed on myeloma cells and allows evading immune recognition by myeloid cells, i.e. monocytes, macrophages and neutrophils. Binding of CD47 to SIRPα expressed on myeloid cells provides a strong 'don't eat me' signal and diminishes phagocytosis of tumor cells. Blocking the CD47-SIRPα axis, by a monoclonal antibody against CD47 or a SIRPα-Fc fusion protein can restore recognition of tumor cells by macrophages and enhance phagocytosis. In patients with Non-Hodgkin's lymphoma the combination of CD20 antibody rituximab with CD47 antibody magrolimab was clinically successful (Advani et al., NEJM 379:1711, 2018). To test the applicability of blocking the CD47-SIRPα axis and improve ADCP of myeloma cells by CD38-targeting or SLAMF7-directed myeloma antibodies, we generated a CD47 IgG2σ antibody carrying an engineered Fc domain not binding to Fcγ receptors (FcγR). This CD47 antibody was subsequently used in phagocytosis experiments in combination with antibodies daratumumab, isatuximab as well as elotuzumab and various myeloma cell lines. The cell lines AMO-1, JK-6L, L363, RPMI-8226, and U266 express different levels of CD47, CD38 and SLAMF7 as determined by quantitative flow cytometry. M0 macrophages expressing FcγRs were generated from healthy donor PBMC monocytes by cultivation with M-CSF for 10-14 days prior use in 6 hour real-time live cell imaging phagocytosis experiments with pHrodo-labeled myeloma cells - turning red only when engulfed by macrophages. Macrophages and myeloma cells were used at an effector-to-target cell ratio of 1:1. Importantly, ADCP of myeloma cells induced by all three monoclonal antibodies, daratumumab, isatuximab or elotuzumab, can be enhanced by the addition of the CD47 blocking antibody. However, improvement in phagocytosis strongly differs between myeloma cell lines although all have high CD47 level on their cell surface. In responsive myeloma cell lines, ADCP mediated by CD38 antibodies daratumumab or isatuximab was found more efficient than that by SLAMF7 antibody elotuzumab. This may be related to the significantly higher CD38 than SLAMF7 expression at the myeloma cell surface. Our findings demonstrate that ADCP of approved IgG antibodies targeting CD38 or SLAMF7 can be enhanced by blocking the CD47-SIRPα axis and this may depend on the particular malignant plasma cell phenotype. The inhibition of this myeloid 'don't eat me' signal with a CD47 blocking antibody may open a new avenue for powerful myeloma immunotherapy. Since combination treatments with proteasome inhibitors and IMiDs are commonly used, these interactions also require attention. Initial data indicate that pre-treatment of myeloma cells with proteasome inhibitor carfilzomib did not negatively impact improvement of ADCP by blocking the CD47-SIRPα axis in responsive cell lines. Taken together, particularly CD38-targeting antibodies may have a significant potential to further improve immunotherapy in multiple myeloma patients. Disclosures No relevant conflicts of interest to declare.
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Weissman, Irving. "Evolution of normal and neoplastic tissue stem cells: progress after Robert Hooke." Philosophical Transactions of the Royal Society B: Biological Sciences 370, no. 1680 (October 19, 2015): 20140364. http://dx.doi.org/10.1098/rstb.2014.0364.

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The appearance of stem cells coincides with the transition from single-celled organisms to metazoans. Stem cells are capable of self-renewal as well as differentiation. Each tissue is maintained by self-renewing tissue-specific stem cells. The accumulation of mutations that lead to preleukaemia are in the blood-forming stem cell, while the transition to leukaemia stem cells occurs in the clone at a progenitor stage. All leukaemia and cancer cells escape being removed by scavenger macrophages by expressing the 'don't eat me' signal CD47. Blocking antibodies to CD47 are therapeutics for all cancers, and are currently being tested in clinical trials in the US and UK.
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Hawkins, Lois A., and Andrew Devitt. "Current Understanding of the Mechanisms for Clearance of Apoptotic Cells—A Fine Balance." Journal of Cell Death 6 (January 2013): JCD.S11037. http://dx.doi.org/10.4137/jcd.s11037.

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Apoptosis is an important cell death mechanism by which multicellular organisms remove unwanted cells. It culminates in a rapid, controlled removal of cell corpses by neighboring or recruited viable cells. Whilst many of the molecular mechanisms that mediate corpse clearance are components of the innate immune system, clearance of apoptotic cells is an anti-inflammatory process. Control of cell death is dependent on competing pro-apoptotic and anti-apoptotic signals. Evidence now suggests a similar balance of competing signals is central to the effective removal of cells, through so called ‘eat me’ and ‘don't eat me’ signals. Competing signals are also important for the controlled recruitment of phagocytes to sites of cell death. Consequently recruitment of phagocytes to and from sites of cell death can underlie the resolution or inappropriate propagation of cell death and inflammation. This article highlights our understanding of mechanisms mediating clearance of dying cells and discusses those mechanisms controlling phagocyte migration and how inappropriate control may promote important pathologies.
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Tsuji, Takahiro, Hiroaki Wake, Mariko Shindo, Daisuke Kato, Hiroaki Ozasa, and Toyohiro Hirai. "Abstract 3451: Microglial phagocytosis suppressed the development of metastatic tumors in the imaging model of brain metastasis." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3451. http://dx.doi.org/10.1158/1538-7445.am2022-3451.

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Abstract Brain metastasis of lung cancer is a crucial problem that causes poor clinical outcomes and alters patient quality of life. Previous evidence showed that lung cancer cells (LUCs) may escape from host immunity to form distant metastases. We previously used an original imaging model of brain metastasis (IBrM) to show a heterogeneous interaction between microglia, the tissue macrophages in the brain, and LUCs in the brain niche. The findings confirmed that microglia can phagocytose metastatic cancer cells. Here, we show that genetic deletion of the “don’t eat me” signals of cancer cells can promote phagocytic activity of microglia against LUCs. We injected an adenocarcinoma lung cancer cell line expressing mCherry (CMT167mC) via the internal carotid artery of the CX3CR1-EGFP mice, whose microglia had been specifically labeled with EGFP. The microglia and LUCs were visualized in vivo simultaneously by two-photon microscopy for 14 days. The tumor fate and microglial response against cancer cells were evaluated at single cell resolution in the IBrM. CD24, CD47, and/or PDL1 were deleted in CMT167mC cells using CRISPR/Cas9 to examine the effect of the “don’t eat me” signals. The dynamic behavior of LUCs and the microglial phagocytosis activity against LUCs were visualized in living mice. Microglial phagocytosis was significantly increased by single deletion of CD47 or CD24 compared with WT cells. Combined deletion of CD47 and CD24 also synergically increased microglial phagocytosis, resulting in reduced IBrM and prolonged mouse survival. By contrast, deletion of PD-L1 did not enhance microglial phagocytosis or prolong survival. The pharmacological or genetic conditional depletion of microglia canceled both the increased phagocytosis and the extended survival time, suggesting that the effect of “don't eat me” signals was microglia-dependent. These results indicate that suppression of both CD24 and CD47 in LUCs enhances microglial phagocytic activity and suppresses the metastatic formation of LUCs. Furthermore, the combined use of CRISPR/Cas9 in LUCs and in vivo imaging allows us to evaluate potential therapeutic targets associated with microglial phagocytosis. We are currently using single cell RNA-seq and cell-to-cell communication analysis of the brain tumor and surrounding niche to explore other signal pathways that regulate tumor phagocytosis by microglia and to identify potential therapeutic targets. Citation Format: Takahiro Tsuji, Hiroaki Wake, Mariko Shindo, Daisuke Kato, Hiroaki Ozasa, Toyohiro Hirai. Microglial phagocytosis suppressed the development of metastatic tumors in the imaging model of brain metastasis [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 3451.
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Theruvath, Johanna, Christopher Mount, Michelle Monje, Crystal Mackall, and Robbie Majzner. "IMMU-55. GD2 IS A MACROPHAGE CHECKPOINT MOLECULE AND COMBINED GD2/CD47 BLOCKADE RESULTS IN SYNERGISTIC EFFECTS AGAINST GD2 POSITIVE MALIGNANCIES." Neuro-Oncology 22, Supplement_2 (November 2020): ii116. http://dx.doi.org/10.1093/neuonc/noaa215.484.

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Abstract GD2 is a disialoganglioside expressed on a variety of tumors including DIPG, neuroblastoma and osteosarcoma. Anti-GD2 antibodies have demonstrated some success in neuroblastoma and they have either not proven to be effective or have not been evaluated in other GD2 positive malignancies. CD47 is the dominant “Don’t Eat Me” signal expressed by cancer cells to inhibit macrophages and blocking CD47 leads to phagocytosis of tumor cells. We hypothesized that CD47 blockade synergizes with anti-GD2. We measured in vitro phagocytosis of DIPG and NBL cells and observed a synergy of anti-GD2/CD47 compared to the single agents. In vivo, this combination led to the complete clearance of both orthotopic and metastatic models of NBL. Additionally, the combination significantly enhanced survival of OS xenografts. Finally, in a murine model of metastatic pulmonary OS, the combination led to a near elimination of all metastatic burden. To understand the underlying biologic basis, we studied the effects of GD2 crosslinking on tumor cells and the effects of GD2 blockade on macrophages. A portion of DIPG or NBL cells die when treated with dinutuximab, and those that survive upregulate surface calreticulin, an important pro-phagocytic (“Eat Me”) signal. Additionally, we have identified the ligand for GD2, a molecule expressed on macrophages known to inhibit phagocytosis. In summary, we have identified a novel combination of anti-GD2 and anti-CD47 antibodies that is highly effective in preclinical models and will soon be tested in children. Furthermore, we have shown that GD2 itself is a macrophage checkpoint or “Don’t Eat Me” signal.
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Schürch, Christian M., Stefan Forster, Frido Brühl, Sara H. Yang, Emanuela Felley-Bosco, and Ekkehard Hewer. "The “don't eat me” signal CD47 is a novel diagnostic biomarker and potential therapeutic target for diffuse malignant mesothelioma." OncoImmunology 7, no. 1 (September 21, 2017): e1373235. http://dx.doi.org/10.1080/2162402x.2017.1373235.

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Aroldi, Andrea, Mario Mauri, Matteo Villa, Federica Malighetti, Federica Cocito, Claudia Voena, Roberto Chiarle, Luca Mologni, Rocco Piazza, and Carlo Gambacorti-Passerini. "Effects of CD24 "Don't Eat Me" Signal Blockade in Combination with Anti-CD47 and Rituximab in Mantle-Cell Lymphoma." Blood 140, Supplement 1 (November 15, 2022): 3136–38. http://dx.doi.org/10.1182/blood-2022-159247.

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Elward, K. "“Eat me” and “don't eat me” signals govern the innate immune response and tissue repair in the CNS: emphasis on the critical role of the complement system." Molecular Immunology 40, no. 2-4 (September 2003): 85–94. http://dx.doi.org/10.1016/s0161-5890(03)00109-3.

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Altevogt, Peter, Marei Sammar, Laura Hüser, Viktor Umansky, and Jochen Utikal. "Perspective – Escape from destruction: how cancer-derived EVs are protected from phagocytosis." Extracellular vesicles as biomarkers – in pathophysiology, physical education and home office? 2, no. 1 (September 2, 2020): 60–64. http://dx.doi.org/10.47184/tev.2020.01.08.

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There is evidence that cancer-derived extracellular vesicles (EVs) have nearby and distant effects in the body. In order to reach distant sites, EVs need to travel through the blood stream and organs where they encounter a hostile environment in the form or phagocytic cells. However, the stability and homeostasis in the blood circulation and in the tumor microenvironment are not well understood. Phagocytosis is an important mechanism for the clearance of apoptotic and necrotic cells. As exosomes (small EV) express “eat-me” signals such as phosphatidyl-serine, it is likely that they are cleared similar to dead cells. Here we discuss measures that cancer cells have developed to protect their EVs from rapid depletion. The expression of “don’t eat me” signals such as CD47 and CD24 on the tumor cell surface and in released exosomes is of vital importance. We will focus on the role of the CD24-Siglec-10 binding axis as a stop signal at the interface between tumor cells and phagocytic cells. Extending the lifetime of EVs is essential for the cancer to achieve systemic immune suppression and to prepare metastatic niches for spreading. Keywords: CD24, CD47, Extracellular vesicles, Siglecs, carbohydrates, phagocytosis
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Litvack, Michael L., and Nades Palaniyar. "Review: Soluble innate immune pattern-recognition proteins for clearing dying cells and cellular components: implications on exacerbating or resolving inflammation." Innate Immunity 16, no. 3 (June 2010): 191–200. http://dx.doi.org/10.1177/1753425910369271.

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Soluble innate immune pattern-recognition proteins (sPRPs) identify non-self or altered-self molecular patterns. Dying cells often display altered-self arrays of molecules on their surfaces. Hence, sPRPs are ideal for recognizing these cells and their components. Dying cell surfaces often contain, or allow the access to different lipids, intracellular glycoproteins and nucleic acids such as DNA at different stages of cell death. These are considered as ‘eat me’ signals that replace the native ‘don’t eat me’ signals such as CD31, CD47 present on the live cells. A programmed cell death process such as apoptosis also generates cell surface blebs that contain intracellular components. These blebs are easily released for effective clearance or signalling. During late stages of cell death, soluble components are also released that act as ‘find me’ signal (e.g. LysoPC, nucleotides). The sPRPs such as collectins, ficolins, pentraxins, sCD14, MFG-E8, natural IgM and C1q can effectively identify some of these specific molecular patterns. The biological end-point is different depending on sPRP, tissue, stage of apoptosis and the type of cell death. The sPRPs that reside in the immune-privileged surfaces such as lungs often act as opsonins and enhance a silent clearance of dying cells and cellular material by macrophages and other phagocytic cells. Although the recognition of these materials by complement-activating proteins could amplify the opsonic signal, this pathway may aggravate inflammation. Clear understanding of the involvement of specific sPRPs in cell death and subsequent clearance of dying cell and their components is essential for devising appropriate treatment strategies for diseases involving infection, inflammation and auto-antibody generation.
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Atkin-Smith, Georgia K. "Phagocytic clearance of apoptotic, necrotic, necroptotic and pyroptotic cells." Biochemical Society Transactions 49, no. 2 (April 12, 2021): 793–804. http://dx.doi.org/10.1042/bst20200696.

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Although millions of cells in the human body will undergo programmed cell death each day, dying cells are rarely detected under homeostatic settings in vivo. The swift removal of dying cells is due to the rapid recruitment of phagocytes to the site of cell death which then recognise and engulf the dying cell. Apoptotic cell clearance — the engulfment of apoptotic cells by phagocytes — is a well-defined process governed by a series of molecular factors including ‘find-me’, ‘eat-me’, ‘don't eat-me’ and ‘good-bye’ signals. However, in recent years with the rapid expansion of the cell death field, the removal of other necrotic-like cell types has drawn much attention. Depending on the type of death, dying cells employ different mechanisms to facilitate engulfment and elicit varying functional impacts on the phagocyte, from wound healing responses to inflammatory cytokine secretion. Nevertheless, despite the mechanism of death, the clearance of dying cells is a fundamental process required to prevent the uncontrolled release of pro-inflammatory mediators and inflammatory disease. This mini-review summarises the current understandings of: (i) apoptotic, necrotic, necroptotic and pyroptotic cell clearance; (ii) the functional consequences of dying cell engulfment and; (iii) the outstanding questions in the field.
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McCracken, Melissa N., Adriel C. Cha, and Irving L. Weissman. "Molecular Pathways: Activating T Cells after Cancer Cell Phagocytosis from Blockade of CD47 “Don't Eat Me” Signals." Clinical Cancer Research 21, no. 16 (June 26, 2015): 3597–601. http://dx.doi.org/10.1158/1078-0432.ccr-14-2520.

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Schürch, C., M. Roelli, M. Wasmer, F. Brühl, S. Forster, R. Maire, S. Di Pancrazio, et al. "PO-171 The "don’t eat me" signal CD47 - a therapeutic option in human anaplastic thyroid carcinoma?" Radiotherapy and Oncology 132 (March 2019): 91. http://dx.doi.org/10.1016/s0167-8140(19)30337-8.

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Maute, Roy Louis, James Y. Chen, Kristopher David Marjon, Jiaqi Duan, Timothy Choi, Mark Chao, Chris H. Takimoto, Balaji Agoram, and Jens-Peter Volkmer. "Translational Study of Cell Surface Proteins in Non-Hodgkin Lymphoma Patients Treated with the First-in-Class Anti-CD47 Antibody Magrolimab (5F9) in Combination with Rituximab." Blood 134, Supplement_1 (November 13, 2019): 5229. http://dx.doi.org/10.1182/blood-2019-127526.

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Introduction Magrolimab (Hu5F9-G4, 5F9) is a first-in-class IgG4 antibody targeting CD47, a macrophage immune checkpoint and "don't eat me" signal expressed on cancer cells. Blockade of CD47 leads to phagocytosis of tumor cells. Magrolimab synergizes with rituximab to eliminate CD20-positive lymphoma by enhancing antibody-dependent cellular phagocytosis. Magrolimab +rituximab demonstrated encouraging safety and efficacy in a Phase (Ph)1b dose escalation cohort in patients with relapsed/refractory (r/r) DLBCL and FL that were rituximab-refractory (Advani et al., NEJM 2018). CD24 is an additional "don't eat me" signal, and has been proposed as a potential target for immunotherapy (Barkal et al. Nature 2019). Here we describe immunohistochemical analysis of CD47 and CD24 in primary patient biopsies from an ongoing follow-up Phase 2 trial of Non-Hodgkin's lymphoma (including DLBCL and indolent lymphoma) patients treated with magrolimab+rituximab. Results By immunohistochemistry, 54 out of 54 patients assessed were positive for expression of CD47 at screening. High levels of CD47 expression were maintained during treatment with clinically-efficacious doses of magrolimab. Therapeutic response did not correlate with CD47 H-score expression levels. At screening, patients presented with highly variable levels of CD24 expression, with 40 of 54 samples showing positive staining in >30% of cells. We observed no significant correlation between CD24 expression by H-score and response to therapy (complete response + partial response) in either DLBCL or indolent lymphoma. Conclusions CD47 shows consistently high expression in primary biopsies from Non-Hodgkin's lymphoma patients and remains persistently high during treatment. In our Phase 2 trial, therapeutic response did not correlate with CD47 expression levels, suggesting that the degree of target expression is not a primary driver of magrolimab efficacy in Non-Hodgkin's lymphoma. Although we observe wide variation in CD24 expression within this cohort, its levels are not predictive of outcome for this disease indication. We are evaluating the expression of additional biomarkers to identify those Non-Hodgkin's lymphoma patients most likely to benefit from magrolimab+rituximab combination therapy. Disclosures Maute: Forty Seven Inc.: Employment, Equity Ownership, Patents & Royalties. Chen:Forty Seven Inc.: Consultancy, Equity Ownership. Marjon:Forty Seven Inc.: Employment, Equity Ownership. Duan:Forty Seven Inc.: Employment, Equity Ownership. Choi:Forty Seven Inc.: Employment, Equity Ownership. Chao:Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties. Takimoto:Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties. Agoram:Forty Seven Inc.: Employment, Equity Ownership. Volkmer:Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties.
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Nakamura, Kyohei, Mika Casey, Harald Oey, Frank Vari, John Stagg, Maher K. Gandhi, and Mark J. Smyth. "Targeting an adenosine-mediated “don’t eat me signal” augments anti-lymphoma immunity by anti-CD20 monoclonal antibody." Leukemia 34, no. 10 (April 8, 2020): 2708–21. http://dx.doi.org/10.1038/s41375-020-0811-3.

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Zuo, Haoxiao, Satwinder Kaur Singh, Marie-José Van Lierop, Jorn Kaspers, Remco Bos, Alwin Kamermans, Helga E. de Vries, et al. "219 CD47 and phosphatidylserine contribute to the interaction between antigen presenting cells and the allogeneic cell-based relapse vaccine DCP-001." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A232. http://dx.doi.org/10.1136/jitc-2021-sitc2021.219.

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BackgroundDCP-001 is a cancer relapse vaccine derived from the DCOne® human leukemic cell line. During manufacturing, DCOne® cells are shifted towards a mature dendritic cell (mDC) phenotype, combining an endogenous tumor antigen repertoire (e.g. WT-1, RHAMM and PRAME) with a mDC costimulatory profile and providing the basis for the highly immunogenic vaccine DCP-001. In a phase I clinical study in acute myeloid leukemia (AML), DCP-001 demonstrated to be safe and to induce multifunctional antitumor immune responses.1 It has also been reported that DCP-001 induces antitumor immunity against multiple myeloma cells in peripheral blood mononuclear cells (PBMC) from multiple myeloma patients and that DCP-001 antigenic material is transferred to host antigen presenting cells (APC), possibly via extracellular vesicles.2 However, the possibility of direct interactions between DCP-001 and host APC has not yet been investigated.MethodsTo further elucidate the mode of action of DCP-001, we studied the interactions of DCP-001 with human PBMC and isolated immature monocyte-derived DCs (iMoDC) in in vitro co-culture studies. A human skin explant model was used to determine uptake of DCP-001 by migrating skin DCs after intradermal injection.ResultsWe found that DCP-001 stimulates the secretion of various proinflammatory cytokines (IL-1β, GM-CSF, IFN-γ, IL-2, TNF-α, and IL-6) and chemokines (IL-8 and RANTES) in PBMC. In addition, we demonstrate that DCP-001 is efficiently taken up by iMoDC via direct cell-cell interactions and that this phagocytic process is influenced by ”eat-me” and ”don’t eat me” signaling pathways. Blocking of the ”eat-me” signals calreticulin and phosphatidylserine inhibited the uptake of DCP-001, whereas blockade of the ”don’t eat me” signal CD47 enhanced DCP-001 uptake. After intradermal injection of DCP-001 in an ex-vivo human skin model, its uptake by skin-emigrating DCs was demonstrated as well as simultaneous activation of these DCs.ConclusionsOur data suggest a key role for host antigen presenting cells in the triggering of immune responses upon DCP-001 vaccination. In addition, the data provide rationale for potential combination therapies based on DCP-001 and inhibitors of the CD47 pathway.Referencesvan de Loosdrecht AA, et al. A novel allogeneic off-the-shelf dendritic cell vaccine for post-remission treatment of elderly patients with acute myeloid leukemia. Cancer Immunol Immunother 2018;67(10):1505–1518.Leaf RK, et al. DCOne as an allogeneic cell-based vaccine for multiple myeloma. J Immunother 2017;40(9):315–322.
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Nguyen, Oanh Thi-Kieu, Anh Nguyen Tu Bui, Ngoc Bich Vu, and Phuc Van Pham. "ID: 1077 Overexpress of CD47 does not alter stemness of MCF-7 breast cancer cells." Biomedical Research and Therapy 4, S (September 5, 2017): 163. http://dx.doi.org/10.15419/bmrat.v4is.351.

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Background: CD47 is a transmembrane glycoprotein expressed on all cells in the body and particularly overexpressed on cancer cells and cancer stem cells of both hematologic and solid malignancies. In the immune system, CD47 acts as a "don't eat me" signal, inhibiting phagocytosis by macrophages by interaction with signal regulatory protein α (SIRPα). In cancer, CD47 promotes tumor invasion and metastasis. This study aimed to evaluate the stemness of breast cancer cells when CD47 is overexpressed. Methods: MCF-7 breast cancer cells were transfected with plasmid pcDNA3.4-CD47 containing the CD47 gene. The stemness of the transduced MCF7 cell population was evaluated by expression of CD44 and CD24 markers, anti-tumor drug resistance and mammosphere formation Results: Transfection of plasmid pcDNA3.4-CD47 significantly increased the expression of CD47 in MCF-7 cells. The overexpression of CD47 in transfected MCF-7 cells led to a significant increase in the CD44+CD24- population, but did not increase doxorubicin resistance of the cells or their capacity to form mammospheres. Conclusion: CD47 overexpression enhances the CD44+CD24- phenotype of breast cancer cells as observed by an increase in the CD44+CD24- expressing population. However, these changes are insufficient to increase the stemness of breast cancer cells.
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Upton, Rosalynd, Allison Banuelos, Dongdong Feng, Tanuka Biswas, Kevin Kao, Kelly McKenna, Stephen Willingham, et al. "Combining CD47 blockade with trastuzumab eliminates HER2-positive breast cancer cells and overcomes trastuzumab tolerance." Proceedings of the National Academy of Sciences 118, no. 29 (July 13, 2021): e2026849118. http://dx.doi.org/10.1073/pnas.2026849118.

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Trastuzumab, a targeted anti-human epidermal-growth-factor receptor-2 (HER2) monoclonal antibody, represents a mainstay in the treatment of HER2-positive (HER2+) breast cancer. Although trastuzumab treatment is highly efficacious for early-stage HER2+ breast cancer, the majority of advanced-stage HER2+ breast cancer patients who initially respond to trastuzumab acquire resistance to treatment and relapse, despite persistence of HER2 gene amplification/overexpression. Here, we sought to leverage HER2 overexpression to engage antibody-dependent cellular phagocytosis (ADCP) through a combination of trastuzumab and anti-CD47 macrophage checkpoint immunotherapy. We have previously shown that blockade of CD47, a surface protein expressed by many malignancies (including HER2+ breast cancer), is an effective anticancer therapy. CD47 functions as a “don’t eat me” signal through its interaction with signal regulatory protein-α (SIRPα) on macrophages to inhibit phagocytosis. Hu5F9-G4 (magrolimab), a humanized monoclonal antibody against CD47, blocks CD47’s “don’t eat me” signal, thereby facilitating macrophage-mediated phagocytosis. Preclinical studies have shown that combining Hu5F9-G4 with tumor-targeting antibodies, such as rituximab, further enhances Hu5F9-G4’s anticancer effects via ADCP. Clinical trials have additionally demonstrated that Hu5F9-G4, in combination with rituximab, produced objective responses in patients whose diffuse large B cell lymphomas had developed resistance to rituximab and chemotherapy. These studies led us to hypothesize that combining Hu5F9-G4 with trastuzumab would produce an anticancer effect in antibody-dependent cellular cytotoxicity (ADCC)-tolerant HER2+ breast cancer. This combination significantly suppressed the growth of ADCC-tolerant HER2+ breast cancers via Fc-dependent ADCP. Our study demonstrates that combining trastuzumab and Hu5F9-G4 represents a potential new treatment option for HER2+ breast cancer patients, even for patients whose tumors have progressed after trastuzumab.
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Li, Jingling, Thomas Brickler, Allison Banuelos, Kristopher Marjon, Anna Shcherbina, Sravani Banerjee, Jing Bian, Cyndhavi Narayanan, Irving L. Weissman, and Sundari Chetty. "Overexpression of CD47 is associated with brain overgrowth and 16p11.2 deletion syndrome." Proceedings of the National Academy of Sciences 118, no. 15 (April 8, 2021): e2005483118. http://dx.doi.org/10.1073/pnas.2005483118.

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Copy number variation (CNV) at the 16p11.2 locus is associated with neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia. CNVs of the 16p gene can manifest in opposing head sizes. Carriers of 16p11.2 deletion tend to have macrocephaly (or brain enlargement), while those with 16p11.2 duplication frequently have microcephaly. Increases in both gray and white matter volume have been observed in brain imaging studies in 16p11.2 deletion carriers with macrocephaly. Here, we use human induced pluripotent stem cells (hiPSCs) derived from controls and subjects with 16p11.2 deletion and 16p11.2 duplication to understand the underlying mechanisms regulating brain overgrowth. To model both gray and white matter, we differentiated patient-derived iPSCs into neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs). In both NPCs and OPCs, we show that CD47 (a “don’t eat me” signal) is overexpressed in the 16p11.2 deletion carriers contributing to reduced phagocytosis both in vitro and in vivo. Furthermore, 16p11.2 deletion NPCs and OPCs up-regulate cell surface expression of calreticulin (a prophagocytic “eat me” signal) and its binding sites, indicating that these cells should be phagocytosed but fail to be eliminated due to elevations in CD47. Treatment of 16p11.2 deletion NPCs and OPCs with an anti-CD47 antibody to block CD47 restores phagocytosis to control levels. While the CD47 pathway is commonly implicated in cancer progression, we document a role for CD47 in psychiatric disorders associated with brain overgrowth.
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Tal, Michal Caspi, Paige Hansen, Nitya Ramadoss, Regan Volk, Balyn Zaro, and Irving L. Weissman. "P66 is a bacterial “don’t eat me signal” that mimics mammalian CD47 and facilitates immune evasion by Borrelia burgdorferi." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 163.36. http://dx.doi.org/10.4049/jimmunol.208.supp.163.36.

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Abstract Innate immunity, the first line of defense against pathogens, relies on efficient elimination of the invading agents by phagocytes. Thus in the co-evolution of host and pathogen, pathogens developed mechanisms to dampen and evade phagocytic clearance. Here, we report that bacterial pathogens can evade clearance by macrophages through molecular mimicry of a mammalian anti-phagocytic “don’t eat me” signal. Using a high affinity structural probe for human CD47, a dominant “don’t eat me” signal, we discovered a bacterial protein that mimics CD47’s structure on the surface of Borrelia burgdorferi (Bb), a bacterial spirochete that can establish infection in mammals including Lyme Disease (LD). Blockade of the mimic promotes clearance of the infection in vivo. We identified P66, a known virulence factor, as the bacterial mimic of CD47. Finally, we determined that patients who return to health following LD infection are more likely to generate antibodies to p66 compared to patients who do not. This study demonstrates molecular mimicry as a means used by Bb to inhibit macrophages and evade phagocytic clearance; this mechanism may have broad implications for understanding host-pathogen interactions and the development of therapeutic strategies to combat bacterial infection. Research reported in this publication was supported by the Fairbairn family foundation; Bay Area Lyme Foundation; the Younger family foundation; the Robert J. Kleberg, Jr., and Helen C. Kleberg Foundation; the Virginia and D. K. Ludwig Fund for Cancer Research; AML grant R01CA086017; the PCBC from NIHLB U01HL099999; as well as grant U19AI109662. M.C.T. was supported by Stanford Immunology training grant 5T32AI007290, and the NIH NRSA 1 F32 AI124558-01 award. L.B.T.D. was supported by a Stanford Diversifying Academia Recruiting Excellence fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Gamboa, Nicholas, Cordell Baker, Osama Youssef, and Samuel Cheshier. "IMMU-37. ANTI-CD47 TREATMENT POTENTIATES PHAGOCYTOSIS OF MEDULLOBLASTOMA BY M1 POLARIZED MACROPHAGES FOLLOWING IRRADIATION." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii139. http://dx.doi.org/10.1093/neuonc/noac209.534.

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Abstract Medulloblastoma (MB) is the most common malignant brain tumor of childhood and accounts for 15–20% of all pediatric brain tumors. Despite significant advancements over the last decade in our understanding of the molecular underpinnings of MB, the overall risk of recurrence remains high, prognosis remains poor, and available treatment modalities remain limited for patients with this disease. Accordingly, the area of targeting tumor immune resistance has garnered increasing interest as a potentially safe and effective adjunctive therapy. CD47 is a cell surface protein that acts as a primary “don’t eat me” signal to the innate immune system and has been shown to be crucial in allowing tumor cells to evade phagocytosis by tumor-associated macrophages. Several preclinical studies aimed at blocking this “don’t eat me signal” through the application of a mouse anti-human monoclonal antibody (Ab) to CD47 (anti-CD47) have shown promise in pediatric brain tumor models. Further, chemotherapy and irradiation have been shown to increase the expression of pro-phagocytic signals on the surfaces of tumor cells. The authors examined the use of anti-CD47 Ab on the rates of phagocytosis of MB cells undergoing different single-fraction doses of external beam irradiation in vitro. The use of anti-CD47 Ab in the D425 MB cell line phagocytosis assay significantly increased rates of phagocytosis for 0 Gy (4.1% without vs. 20.3% with anti-CD47 Ab; p &lt; 0.0001), 2 Gy (7.4% without vs. 23.4% with anti-CD47 Ab; p &lt; 0.0001), 5 Gy (11.9% without vs. 27.3% with anti-CD47 Ab; p &lt; 0.0001), 10 Gy (21.7% without vs. 34% with anti-CD47 Ab; p &lt; 0.0001), and 20 Gy treatment groups (27.2% without vs. 43.9% with anti-CD47 Ab; p &lt; 0.0001). A similar pattern of phagocytosis potentiation through use of anti-CD47 Ab with increasing doses of radiation was seen in D458 and D341 MB cell lines.
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Tian, Lei, Bo Xu, Kun-Yu Teng, Mihae Song, Zheng Zhu, Yuqing Chen, Jing Wang, et al. "Targeting Fc Receptor-Mediated Effects and the “Don't Eat Me” Signal with an Oncolytic Virus Expressing an Anti-CD47 Antibody to Treat Metastatic Ovarian Cancer." Clinical Cancer Research 28, no. 1 (October 13, 2021): 201–14. http://dx.doi.org/10.1158/1078-0432.ccr-21-1248.

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Piao, Longzhu, Susheela Tridandapani, and S. Joseph Huang. "Phagocytic activity of macrophages is regulated by first trimester decidual cells in response to pro-inflammatory stimuli via the modulation of “Don't-Eat-Me” signal." Placenta 35, no. 9 (September 2014): A57—A58. http://dx.doi.org/10.1016/j.placenta.2014.06.187.

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Anandan, Vinitha, Thushara Thulaseedharan, Aishwarya Suresh Kumar, Karthika Chandran Latha, Amjesh Revikumar, Ajit Mullasari, Chandrasekharan C. Kartha, Abdul Jaleel, and Surya Ramachandran. "Cyclophilin A Impairs Efferocytosis and Accelerates Atherosclerosis by Overexpressing CD 47 and Down-Regulating Calreticulin." Cells 10, no. 12 (December 20, 2021): 3598. http://dx.doi.org/10.3390/cells10123598.

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Impairment of efferocytosis in apoptotic macrophages is a known determinant of the severity of atherosclerosis and the vulnerability of plaques to rupture. The precise mechanisms involved in impaired efferocytosis are unclear. Given the well-recognized role of the inflammatory cytokine cyclophilin A (Cyp A) in modulating several atherogenic mechanisms in high-glucose primed monocytes, we investigated the role of Cyp A in macrophage efferocytosis. The efficiency of efferocytosis in RAW 264.7 macrophages grown in vitro and primed with cyclophilin A was assessed using flow cytometry and confocal assays. Cholesterol content in cells was measured using cell-based cholesterol efflux assay. Proteomic analysis and bioinformatics tools were employed to decipher the link between cyclophilin A and the known ligand receptors involved in efferocytosis. Cyclophilin A was found to impair efferocytosis in apoptotic macrophages by reducing ABCA1-mediated cholesterol efflux in foam cells derived from macrophages. Cyclophilin A-primed macrophages showed an increase in expression of the don’t-eat-me signal CD 47 and a decrease in the expression of the eat-me signal, calreticulin. Phagocytosis was restored upon silencing of cyclophilin A. New Zealand white rabbits were fed a high-fat diet, and lesions in their aortae were analyzed histologically for evidence of atherosclerosis and the expression of Cyp A, CD 47 and calreticulin, the ligand receptor involved in efferocytosis. Gene and protein expressions in aortae and macrophages were analyzed by real-time PCR and Western blotting. Cyclophilin A, via its effects on the expression of CD 47 and calreticulin, impairs efferocytosis in apoptotic macrophages. Together with its impact on cholesterol efflux from macrophages, these effects can amplify other mechanisms of Cyp A in accelerating the progression of atherosclerosis.
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Kazama, Ryo, Hiroaki Miyoshi, Mai Takeuchi, Kohta Miyawaki, Kazutaka Nakashima, Noriaki Yoshida, Keisuke Kawamoto, et al. "Combination of CD47 and signal‐regulatory protein‐α constituting the “don’t eat me signal” is a prognostic factor in diffuse large B‐cell lymphoma." Cancer Science 111, no. 7 (June 29, 2020): 2608–19. http://dx.doi.org/10.1111/cas.14437.

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Melo Garcia, Luciana, and Frédéric Barabé. "Harnessing Macrophages through the Blockage of CD47: Implications for Acute Myeloid Leukemia." Cancers 13, no. 24 (December 13, 2021): 6258. http://dx.doi.org/10.3390/cancers13246258.

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CD47 is a surface membrane protein expressed by all normal tissues. It is the so-called “don’t eat me signal” because it protects the cells against phagocytosis. The CD47 interacts with the signal regulatory protein alpha (SIRPα) on the surface of macrophages, leading to downstream inhibitory signaling that dampens phagocytic capacity. Since macrophages exert immune surveillance against cancers, cancer cells overexpress CD47 to defend themselves against phagocytosis. Acute myeloid leukemia (AML) is a cancer of hematopoietic stem/progenitor cells (HSPC), and similar to other types of cancers, leukemic blasts show enhanced levels of CD47. In patients with AML, CD47 has been associated with a higher disease burden and poor overall survival. Blockage of CD47-SIRPα signaling leads to improved phagocytosis of AML cells and better overall survival in xenograft models. However, the introduction of a pro-phagocytic signal is needed to induce greater phagocytic capacity. These pro-phagocytic signals can be either Fc receptor stimulants (such as monoclonal antibodies) or natural pro-phagocytic molecules (such as calreticulin). Based on these pre-clinical findings, various clinical trials investigating the blockade of CD47-SIRPα interaction have been designed as monotherapy and in combination with other anti-leukemic agents. In this review, we will discuss CD47 biology, highlight its implications for AML pathophysiology, and explore the potential clinical translation of disrupting CD47-SIRPα to treat patients with AML.
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Cui, Lu, Cristabelle De Souza, Tristan Lerbs, Jessica Poyser, Clarissa Yu, Kerri Rieger, Sally Arai, et al. "Multi-Omics Profiling of Skin Biopsies of Patients with Sclerodermatous Graft-Vs-Host Disease Suggests Therapeutic Potential of Targeting Don't Eat Me Signals." Blood 140, Supplement 1 (November 15, 2022): 272–73. http://dx.doi.org/10.1182/blood-2022-169789.

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43

Nam, Suk Woo, Sangyean Kim, Min Jeong Na, Eunbi Shin, Jin Woong Ha, Soyoung Jeon, and Jeong Hwan Yoon. "Abstract 5165: In vivo therapeutic validation of NRT-YHD_001, a novel macrophage checkpoint inhibitor, in liver cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5165. http://dx.doi.org/10.1158/1538-7445.am2023-5165.

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Abstract Previously, we demonstrated that recovery of Histone deacetylase 6 (HDAC6) elicited let-7i-5p suppression to de-repress the thrombospondin-1 (TSP1) expression, and thereby it occupied CD47 receptor to block CD47-SIRPα mediated anti-phagocytosis of macrophage in liver cancer. NRT-YHD_001 is a modified antisense miRNA of let-7i-5p for liver cancer treatment. NRT-YHD_001 was substituted with O-methoxyethyl and phosphothioate for stability, and N-acetylgalactosamine was attached for specific delivery to the liver. In in vitro phagocytosis assay, NRT-YHD_001 showed macrophage phagocytosis activity with similar or better results compared to non-modified antisense let-7i-5p (AS_let-7i-5p). In addition, it was confirmed that NRT-YHD_001 inhibited endogenous let-7i-5p of liver cancer cells and activated macrophage phagocytosis at 4°C or 25°C for up to 2 weeks. When NRT-YHD_001 activity was investigated in vivo after 1 week, 2 weeks, and 4 weeks after administration of single dose NRT-YHD_001 to the tail vein of a mouse, NRT-YHD_001 was not degraded, and let-7i-5p was inhibited while maintaining activity in liver tissue for 2 weeks after injection. To investigate the in vivo therapeutic effect, a mouse spontaneous (Ras-transgenic) liver cancer model was used and compared with the sorafenib-administered group. After administration of NRT-YHD_001 and sorafenib each week at the time when liver mass was detected, the tumor size and growth rate were compared. As a result, the NRT-YHD_001 administration group showed significant therapeutic effect compared to sorafenib. These results showed that NRT-YHD_001 had a strong anticancer effect by converting the macrophage of don't eat me into eat me signal in the tumor microenvironment of liver cancer, thereby removing or inhibiting liver cancer cells. Keywords: let-7i-5p, macrophage, phagocytosis, liver cancer, NRT-YHD_001 Citation Format: Suk Woo Nam, Sangyean Kim, Min Jeong Na, Eunbi Shin, Jin Woong Ha, Soyoung Jeon, Jeong Hwan Yoon. In vivo therapeutic validation of NRT-YHD_001, a novel macrophage checkpoint inhibitor, in liver cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5165.
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Liu, Mingen, Roddy S. O’Connor, Sophie Trefely, Kathleen Graham, Nathaniel W. Snyder, and Gregory L. Beatty. "Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47−mediated ‘don’t-eat-me’ signal." Nature Immunology 20, no. 3 (January 21, 2019): 265–75. http://dx.doi.org/10.1038/s41590-018-0292-y.

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45

Griffiths, M. R., P. Gasque, and J. W. Neal. "The Regulation of the CNS Innate Immune Response Is Vital for the Restoration of Tissue Homeostasis (Repair) after Acute Brain Injury: A Brief Review." International Journal of Inflammation 2010 (2010): 1–18. http://dx.doi.org/10.4061/2010/151097.

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Neurons and glia respond to acute injury by participating in the CNS innate immune response. This involves the recognition and clearance of “not self ” pathogens and “altered self ” apoptotic cells. Phagocytic receptors (CD14, CD36, TLR–4) clear “not self” pathogens; neurons and glia express “death signals” to initiate apoptosis in T cells.The complement opsonins C1q, C3, and iC3b facilitate the clearance of apoptotic cells by interacting with CR3 and CR4 receptors. Apoptotic cells are also cleared by the scavenger receptors CD14, Prs-R, TREM expressed by glia. Serpins also expressed by glia counter the neurotoxic effects of thrombin and other systemic proteins that gain entry to the CNS following injury. Complement pathway and T cell activation are both regulated by complement regulatory proteins expressed by glia and neurons. CD200 and CD47 are NIRegs expressed by neurons as “don't eat me” signals and they inhibit microglial activity preventing host cell attack. Neural stem cells regulate T cell activation, increase the Treg population, and suppress proinflammatory cytokine expression. Stem cells also interact with the chemoattractants C3a, C5a, SDF-1, and thrombin to promote stem cell migration into damaged tissue to support tissue homeostasis.
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Han, Xiao, Mengning Wang, Songwei Duan, Paul J. Franco, Jennifer Hyoje-Ryu Kenty, Preston Hedrick, Yulei Xia, et al. "Generation of hypoimmunogenic human pluripotent stem cells." Proceedings of the National Academy of Sciences 116, no. 21 (April 30, 2019): 10441–46. http://dx.doi.org/10.1073/pnas.1902566116.

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Polymorphic HLAs form the primary immune barrier to cell therapy. In addition, innate immune surveillance impacts cell engraftment, yet a strategy to control both, adaptive and innate immunity, is lacking. Here we employed multiplex genome editing to specifically ablate the expression of the highly polymorphic HLA-A/-B/-C and HLA class II in human pluripotent stem cells. Furthermore, to prevent innate immune rejection and further suppress adaptive immune responses, we expressed the immunomodulatory factors PD-L1, HLA-G, and the macrophage “don’t-eat me” signal CD47 from the AAVS1 safe harbor locus. Utilizing in vitro and in vivo immunoassays, we found that T cell responses were blunted. Moreover, NK cell killing and macrophage engulfment of our engineered cells were minimal. Our results describe an approach that effectively targets adaptive as well as innate immune responses and may therefore enable cell therapy on a broader scale.
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Astle, John, Yangfei Xiang, Anthony Rongvaux, Carla Weibel, Henchey Elizabeth, Stephanie Halene, In-Hyun Park, and Richard Flavell. "Developing a Model of Human Pluripotent to Hematopoietic Stem Cell Development in Mistrg Mice." Blood 126, no. 23 (December 3, 2015): 4755. http://dx.doi.org/10.1182/blood.v126.23.4755.4755.

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Abstract De novo generation of HSCs has been described as a "holy grail" of stem cell biology, however the factors required for converting human pluripotent stem cells (PSCs) to true hematopoietic stem cells (HSCs) capable of robust long-term engraftment have yet to be fully characterized. Two groups have shown that injection of PSCs into immunodeficient mice leads to teratomas containing niches producing hematopoietic progenitors capable of long-term engraftment. Once these hematopoietic progenitors and their microenvironments are better characterized, this system could be used as a model to help direct in vitro differentiation of PSCs to HSCs. Toward this end, we have injected human PSCs into immunodeficient mice expressing human rather than mouse M-CSF, IL-3, GM-CSF, and thrombopoietin, as well as both human and mouse versions of the "don't eat me signal" Sirpa (collectively termed MISTRG mice). These cytokines are known to support different aspects of hematopoiesis, and thrombopoietin in particular has been shown to support HSC maintenance, suggesting these mice may provide a better environment for human PSC-derived HSCs than the more traditional mice used for human HSC engraftment. The majority of teratomas developed so far in MISTRG contain human hematopoietic cells, and the CD34+ population isolated from over half of the teratomas contained hematopoietic colony forming cells by colony forming assay. These findings further corroborate this approach as a viable method for studying human PSC to HSC differentiation. Disclosures No relevant conflicts of interest to declare.
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Ysebaert, Loic, Emilie Laprevotte, Christian Klein, Guy Laurent, Anne Quillet-Mary, Mary Poupot, and Jean-Jacques Fournié. "“Don't Eat me”: CD47 and LFA-1 Modulate CLL Response to Nurselike Cells-Mediated Antibody-Dependent Phagocytosis Induced by Rituximab and Obinutuzumab (GA101)." Blood 118, no. 21 (November 18, 2011): 1762. http://dx.doi.org/10.1182/blood.v118.21.1762.1762.

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Abstract Abstract 1762 INTRODUCTION AND AIMS: Efficacy of therapeutic monoclonal antibodies depends to a large extent on the induction of effective antibody dependent cell cytotoxicity and phagocytosis (ADCC/ADCP) by CD16A+ immune effector cells. Chao et al. have recently unraveled the role of antibody dependent cell cytotoxicity and phagocytosis (ADCP) in rituximab (RTX)-induced tumor cell clearance using murine models of NHL [Chao M, 2010]. Nurse-like cells (NLC) provide pro-survival signals by direct contact and/or secretion of soluble factors while remaining M2-macrophages by nature [Ysebaert L, 2011]. M2 macrophages rapidly clear multiple opsonized targets [Leidi M, 2009], infiltrate lymph nodes and bone marrow, and are resistant to chemotherapeutic drugs thereby acting as important mediators of anti-CD20 mediated ADCP in CLL. We used an in vitro culture system to assess NLC-mediated ADCP mediated by RTX and obinutuzumab (GA101), a type II, glyco-engineered CD20 antibody with enhanced ADCC/ADCP through improved CD16A binding. METHODS: Antibody-mediated B cell depletion was determined by flow cytometry after antibody treatment. PBMCs from CLL patients were cultured for 14 days to allow outgrowth of NLC [Tsukada N, 2002]. Cells were collected and either (i) put in 6-well plates in the same medium without NLC (w/o NLC), or (ii) seeded back onto NLC (CLL+NLC), before anti-CD20 antibodies were added at 10μg/ml for 7d. For CD47 blocking experiments, cells were incubated for 15 min with blocking antibodies before being seeded back onto NLC. An Affymetrix Uplus2.0 chip was used for gene expression profiling (GEP) of 19 NLC and 5 normal CD14+ monocytes samples. For phenotype studies, CLL cells in suspension were thoroughly harvested with medium, and remaining adherent CLL cells were discarded from NLC by vigorous pipetting, before staining with CD47-FITC/LFA-1-PE antibodies. RESULTS: CONCLUSIONS: Our results suggest that NLC may be therapeutically exploited through mediators of ADCP, especially in lymphoid organs. For that purpose, the combination of CD47 and CD20 antibodies may be considered. Due to its efficacy even in LFA-1hi patients, GA101 is considered a better mediator of NLC-ADCP. Exploring the regulation of CD47 in CLL cells is important because it may interfere with strategies targeting surface antigens through FcgammaR-dependent mechanisms. Disclosures: Ysebaert: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Klein:Roche: Employment, Equity Ownership, Patents & Royalties.
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Mitra, Siddhartha, Daniel Picard, Nan Qin, Allison Cole, Joselyn Cruz Cruz, Viktoria Marquardt, Sujatha Venkataraman, Rajeev Vibhakar, and Marc Remke. "IMMU-38. MYC DRIVEN IMMUNE SUPPRESSION IN GROUP 3 MEDULLOBLASTOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii139. http://dx.doi.org/10.1093/neuonc/noac209.535.

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Abstract BACKGROUND The expression of MYC in tumor cells regulates the tumor microenvironment through innate and adaptive immune effector cells and immune regulatory cytokines. MYC has also been shown to regulate the expression of the immune checkpoint gene products CD47 and programmed death-ligand 1 (PD-L1). While PD-L1 inhibits adaptive immune response, CD47 on tumor cells binds to SIRPa on macrophages and acts as a “Don’t eat me” signal. We have previously shown that blocking the CD47-SIRPa pathway significantly decreases tumor burden and increases survival in five etiologically distinct adult and pediatric brain tumor xenograft models, including Group 3 or MYC-driven MB, by activating macrophage-mediated phagocytosis. METHODS We performed a primary screen including 78 epigenetic inhibitors and a secondary screen including 20 histone deacetylase inhibitors (HDACi) to compare response profiles in ATRT, medulloblastoma (n = 14), and glioblastoma (n = 14). This unbiased approach revealed the preferential activity of Class I HDACi in MYC-driven medulloblastoma mediated by induction of apoptosis, reduction in MYC transcription, and release of pro-inflammatory cytokines in MYC-driven medulloblastoma, with little to no activity in non-MYC-driven medulloblastoma, AT/RT, and glioblastoma in vitro. In addition, we tested the combinatorial effect of directly targeting the MYC/MAX interaction using MYCI-975 and the CD47-SIRPa phagocytosis checkpoint pathway using in-vitro phagocytosis assays and in-vivo xenograft models. In two orthotopic mouse models of MYC-driven medulloblastoma, MYCi975 displayed anti-tumoral effects at the primary site and the metastatic compartment. Furthermore, RNA sequencing revealed NFκB pathway induction as a response to MYC treatment, followed by interferon-gamma (IFN-G) release and cell surface expression of engulfment (“eat-me”) signals (such as calreticulin) and enhanced in vitro phagocytosis and survival in tumor-bearing mice. CONCLUSION Together, these findings suggest a dynamic relationship between MYC amplification and innate immune suppression in MYC-medulloblastoma and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses.
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Andrejeva, Gabriela, Benjamin Capoccia, Rachel Delston, Michael Donio, Ronald Hiebsch, Robyn Puro, Casey Wilson, Arun Kashyap, and Daniel Pereira. "260 CD47 antibody, AO-176 demonstrates potent anti-tumor activity in pre-clinical solid tumor xenografts as a single agent and in combination with multiple classes of therapeutics." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A282. http://dx.doi.org/10.1136/jitc-2021-sitc2021.260.

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BackgroundCD47 is a cell surface protein expressed on tumors that binds SIRPα on macrophages and dendritic cells resulting in a ”don’t eat me” signal that allows tumors to evade phagocytosis. The highly differentiated monoclonal antibody, AO-176 directly targets CD47 and blocks this signal. AO-176 is currently being tested in phase 1 clinical trials in solid tumors and multiple myeloma. The purpose of this study was to assess in vivo efficacy of AO-176 in solid tumor models as a single agent and in combination with multiple classes of therapeutics including chemotherapeutics, monoclonal antibodies and T-cell checkpoint inhibitors.MethodsCD47 expression levels on solid tumor types were assessed by immunohistochemistry using a tumor tissue microarray. Cell-based binding was performed using flow cytometry under acidic and physiologic pH conditions to characterize the functional activity of AO-176 in the two pH environments representing tumor and normal physiologic environments. In vivo studies were performed using models of solid cancers.ResultsAll 12 solid tumor indications assessed were positive for cell membrane localized CD47 (3.3–98.6 H-scores). Cell-based binding of AO-176 to solid cancer cell lines was significantly greater (1.6–25-fold decrease in EC50, 11–39% increase in Bmax) in acidic conditions as compared to a neutral pH environment, demonstrating improved binding in the lower pH environments associated with solid tumors. AO-176 treatment in solid tumor xenograft models resulted in potent anti-tumor activity as a monotherapy (40–58% TGI) and in combination with paclitaxel in an ovarian model (99% TGI), cisplatin in an ovarian model (84% TGI), cisplatin in a gastric model (76% TGI), and an anti-VEGFR-2 in a gastric model (86% TGI). In vivo efficacy of CD47 blockade alone (~33% TGI) and in combination with anti-PD-1 (74% TGI) and anti-PD-L1 (80% TGI) T-cell checkpoint inhibitors was observed in a syngeneic model of colon cancer using a surrogate anti-CD47 blocking antibody.ConclusionsAO-176 is a differentiated anti-CD47 agent that in addition to blocking the don’t eat me signal, directly kills cancer cells, shows lower binding to normal cells such as RBCs and demonstrates increased binding activity in acidic conditions as found in the microenvironment of solid tumors. AO-176 also elicits potent anti-tumor activity in xenograft and syngeneic models as a single agent and in combination with chemotherapies, monoclonal antibodies and T-cell checkpoint inhibitors. AO-176 is currently in clinical trials as a single agent and in combination in patients with select solid cancers (NCT03834948) and in multiple myeloma (NCT04445701).
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