Antibody-mediated disruption of PD-L1 and CMTM6’s interaction in myeloid cells enhances immune activation to promote tumoricidal T cell expansion 2428

Abstract Description Therapies targeting the PD-1/PD-L1 axis are among the leading treatments of cancer, but only a minority of patients benefit. Many therapies focus on preventing PD-L1 from binding to its receptor, PD-1, but do not address PD-L1’s ability to be recycled to the cell surface and any intrinsic functions it may possess. Our lab has developed an antibody (H1A) that binds to PD-L1 and prevents its association with a stabilizing protein, CMTM6, therefore targeting it for lysosomal degradation. Consequently, H1A limits any PD-L1 intrinsic function while also decreasing interactions with PD-1. Here, we use human-derived immune cells to test H1A’s effect on immune responses through flow cytometry, multiplex screening, and cytotoxicity assays. Additionally, we have developed a humanized PD-1/PD-L1 mouse model that allows us to test H1A’s effect on tumor growth inhibition in an immunocompetent host. Our results show that H1A specifically targets human myeloid cells, resulting in increased co-stimulation, antigen presentation, and cytokine secretion. H1A demonstrated enhanced T cell cytotoxicity in a whole PBMC culture. Finally, H1A resulted in greater tumor growth inhibition and survival in our in vivo tumor models. This work highlights the importance of targeting beyond PD-1/PD-L1 ligation and that myeloid cells are instrumental to enhancing the immune response against cancer. H1A is emerging as a new immunotherapy tool to target PD-L1 and CMTM6 in myeloid cells for treatment of cancers. Funding Sources NIH R01 92389022; NIH T32 AI170478; Mayo Clinic Graduate School of Biomedical Sciences Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)