A Glucocorticoid-Fas axis controls immune evasion from pan-cytotoxic lymphocytes during metastatic seeding 2334193

Abstract Introduction Metastasis is the major cause of death for patients with solid malignancies, such as Triple Negative Breast Cancer (TNBC). Metastatic lesions arise from cancer cells that disseminate from the original tumor mass and colonize new organs. While cancer cells in the tumor mass are protected by an immune-suppressive microenvironment, disseminated tumor cells (DTCs) in a new organ are vulnerable to immune attack. How some of these DTCs overcome immune surveillance remains unknown. Methods We used a visible antigen in a model of TNBC with cognate CD8+ T cells to interrogate mechanisms of immune evasion in early metastatic seeding. We focused on the lungs, as a major site of metastasis in TNBC and an organ with an active resident immune system. Results DTCs that escaped T cell killing showed a heightened activation of the Glucocorticoid Receptor (GR). Using a cancer cell specific GR knockdown, we showed that GR activity in DTCs was essential for resistance to both CD8+ T cells and Natural Killer (NK) cells. Notably, GR inhibition did not affect the primary tumor. To uncover how GR activity in DTCs dampened killing by NK and CD8+ T cells, we developed a labelling tool to tag immune cells in the DTC niche. Single cell analysis of these microscopic lesions uncovered Fas-FasL as a key pan-cytotoxic pathway against DTCs. Mechanistically, GR prevents NF-kB mediated expression of the cell death receptor Fas, inhibiting Fas-mediated DTC elimination. Pharmacologic inhibition of GR in combination with immune checkpoint blockade reduced metastatic burden and expanded lifespan in mice. Conclusion Thus, we discovered a mechanism of immune evasion that operates specifically during early metastatic seeding, illustrating the unique immune-cancer interactions at this stage in the metastatic cascade. Our findings suggest that there are therapeutic opportunities to eliminate DTCs, separately from treatments aimed at primary tumors, with GR inhibition as one promising target. Funding Source DOD/CDMRP/BCRP Era of Hope Scholar Expansion Award (W81XWH-14-1-0191), New York Stem Cell Foundation, Ludwig Cancer Center at Harvard and the Parker Institute for Cancer Immunotherapy (PICI) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)