Abstract B017: Chronic stress signaling in disseminated tumor cells promotes immune evasion in breast cancer metastasis

Abstract Breast cancer is one of the most lethal diseases for women, with metastasis accounting for over 90% of mortalities. Metastasis occurs when disseminated tumor cells (DTCs) escape detection and killing by surveilling cytotoxic immune cells. The mechanisms of DTC immune evasion are currently not well understood, and this represents a crucial barrier to developing effective therapies to prevent metastatic disease. In the Agudo Lab, we investigate how DTCs evade immune surveillance by utilizing our JEDI CD8+ T cells, which recognize the Green Fluorescent Protein (GFP) to target tumor cells for killing. We used JEDI T cells in combination with a model of breast cancer dissemination in which the cancer cells express GFP. By profiling the GFP+ DTCs that successfully survive JEDI immune attack, we unexpectedly discovered that chronic stress hormone (glucocorticoid) signaling is a top driver of immune evasion in lung DTCs and micro-metastases. Further analysis revealed that activation of the glucocorticoid receptor (GR) promotes an immune evasive state in DTCs that is independent of the suppressive effect of glucocorticoids on immune cells. Indeed, elevated GR activation signatures in patients with primary breast cancer correlates with worse survival. We determined that GR signaling in disseminated breast cancer cells in the lung directly blocks cytotoxic lymphocyte killing by both CD8+ T cells and NK cells, which increases metastatic burden. Mechanistically, DTCs harness stress hormones to repress the death receptor FAS and acquire an overall anti- apoptotic phenotype in order to protect themselves from immune clearance. We determined that pharmacologic antagonism of GR by Mifepristone treatment synergizes with anti-PD1 immunotherapy to reduce metastasis by promoting cytotoxic killing of DTCs and early micro-metastases. Exploiting the mechanisms by which tumor-intrinsic GR signaling prevents immune responses represents promising new avenues for limiting metastasis, and opens the door for new combinatorial treatments with current immunotherapy regimens. Citation Format: Monica Cassandras, Yu Huang, Ia Codinachs, Xavier Sanchez, Jeffrey Chuong, Adam Getzler, Pilar Baldominos Flores, Judith Agudo. Chronic stress signaling in disseminated tumor cells promotes immune evasion in breast cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B017.