Tumor hypoxia drives immune suppression and immunotherapy resistance
Midan Ai1,2, Priyamvada Jayaprakash1, Todd Bartkowiak1,2, Pratha Budhani1, Jie Sheng1, Casey Ager1,2, Courtney Nicholas1, Ashvin Jaiswal1, Yanqiu Sun1, Krishna Shah1, Anna Zal1, Tomasz Zal1,2, Michael A. Curran1,2*
1Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054
2University of Texas Health Science Center at Houston Graduate School of Biomedical Science, Houston TX, 77054
Tumor hypoxia predicts poor outcomes across all cancers and has long been recognized as a critical source of resistance to both chemotherapy and radiotherapy. Despite the success of T cell immune checkpoint blockade in treating melanoma, aggressive adenocarcinomas of the prostate and pancreas are largely resistant to CTLA-4 and PD-1 antibody therapy in the mouse and in man. We find that hypoxic zones of these tumors resist infiltration by T cells even in the context of robust infiltration of normoxic areas of the same tumor (e.g. in the context of T cell checkpoint blockade). Beyond this lack of accessibility to tumor-specific T cells, hypoxia drives the establishment of a highly interdependent network of immunosuppressive stromal cells. Among these, we find myeloid-derived suppressor cells and myofibroblasts to be the critical populations which act together to suppress T cell responses and mediate immunotherapy resistance.
Using the hypoxia-specific prodrug TH-302, we show that disruption of hypoxia in both transplantable and genetically-engineered murine models of prostate cancer sensitizes them to antibody blockade of CTLA-4 and PD-1. Loss of immune resistance is a consequence of re-oxygenation of hypoxia zones which results in 1) loss of myeloid suppressors, 2) reduced capacity to suppressively polarize new myeloid immigrants, and 3) loss of suppressive activation of myofibroblasts. This combination of hypoxia disruption and T cell checkpoint blockade has immense potential to render some of the most therapeutically resistant cancers sensitive to immunotherapy.
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