Dysfunction of infiltrating CD8+ effector T cells can be induced by hypoxia and aberrant tumor metabolite uptake in the microenvironment causing an “exhausted” T cell phenotype that limits anti-tumor immunosurveilance. Hence- therapeutic strategies aimed at improving T cell bioenergetics have the potential to reinvigorate T cell responses to reduce tumor burden. CD47 is a widely expressed receptor that controls phagocytic activity by engaging its counter receptor, SIRPα, in macrophages. Also autonomously or by binding to its ligand Thrombospondin-1 CD47 activation can control cell fate under stress. Our prior work shows that targeting CD47 on CD8+ T cells enhanced cytotoxicity against cancer cells. Moreover, depletion of CD8+ T cells in murine models reversed the anti-tumor effect of anti-CD47 therapy. Our new data shows that targeting CD47 reduced the growth of B16 melanoma tumors by approximately 50% (1607 ± 213.7, saline vs. 815.1 ± 67.8, CD47 (-) *p<0.02 n=5-6). Further examination of tumors by live photoacoustic imaging showed that tumors of animals treated with anti-CD47 had reduction in oxygen tension and reduced vascularity when compared to control. This suggests that the reduction in tumor hypoxia by CD47 may shift metabolic competition in the microenvironment to increase metabolite availability allowing optimal activation of cytotoxic T cells. Cell respirometry measurements using an Agilent Seahorse bioanalyzer showed increased levels of mitochondrial function and glycolytic flux in CD47 null T cells when compared to WT. Moreover, these cells showed increased mitochondrial density and increased levels of the mitochondrial biogenesis regulator, PGC1-a. Treatment with CD47 antibody enhanced Pmel-1 CD8+ T cell effector function by reducing B16 melanoma target cell viability by over 60%. Anti-CD47 treatment of these T cells also resulted in upregulation of cell bioenergetics, suggesting that targeting CD47 may impact T cell metabolism to enhance cytotoxic activity against cancer cells. Therefore, our studies show a new role of CD47 immunotherapy regulating immunometabolism of T cells to enhance effector function which may lead to improvement of clinical outcomes in melanoma patients.
Citation Format: Yismelin R. Feliz-Mosquea, Elizabeth Stirling, Katherine L. Cook, Adam Wilson, Manish Bharadwaj, Anthony J. Molina, Liliya Yamaleyeva, Pierre L. Triozzi, David R. Soto-Pantoja. Anti-CD47 immunotherapy regulates T cell metabolism and hypoxia in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3528.