CD47-Sirpa blockade enhances antitumor activity against mouse liver cancer by boosting cDC2 functions 4531

Abstract Description The CD47-SIRPα axis functions as an immune checkpoint, transmitting a “don’t eat me” signal to prevent macrophage-mediated phagocytosis of tumor cells. While CD47 is expressed on most immune cells and is highly induced in tumor cells, SIRPα is expressed on phagocytes, including macrophages and type II conventional dendritic cells (cDC2s). Blocking the binding between CD47 and SIRPα is shown to promote antitumor immunity. However, the mechanism of how CD47-Sirpα blockade regulates DC functions is still unclear. Here we demonstrated that anti-CD47 and/or anti-Sirpα antibodies increased the phagocytic activity and antigen presentation of MutuDC2, a cDC2 cell line, against Hepa1-6, a mouse hepatocellular carcinoma cell line expressing LCMV-GP protein. Moreover, CD47 blockade also enhanced BM-derived cDC2 functions in boosting the proliferation and cytotoxic activity of P14 CD8 T cells in vitro. More importantly, anti-CD47 antibodies reduced tumor growth in vivo and cDC2s and IFNγ+ functional CD8 T cells were enriched in the tumor microenvironment compared to isotype control. In conclusion, CD47-Sirpα blockade boosts cDC2 functions, including phagocytic activity, antigen presentation, and cross-presentation ability, eliciting a better antitumor activity in antigen-specific CD8 T cells and emphasizes the therapeutic benefits of immune checkpoint blockade through cDC2. Funding Sources support by NSCCMOH-113C101-92 (Excellent Translational Medicine Research Projects of National Taiwan University College of Medicine, and National Taiwan University Hospita) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)