Immunotherapy Resistant Triple Negative Breast Cancer Utilizes Interferon Gamma Signaling to Evade NK Responses during Metastasis 2335047

Introduction Combination immunotherapy is an approved treatment for stage II-III triple negative breast cancer (TNBC). However, partial responders to immunotherapy develop rapid recurrence and lethal metastatic disease. The mechanisms underlying this relapse and subsequent metastasis are largely unknown. Methods To address this problem we used mouse models to investigate how cancer cells in the primary tumor mass that survive immunotherapy contribute to subsequent recurrence. We found that immunotherapy-resistant cancer cells are more metastatic and more efficiently colonize distal organs. Molecular characterization of these cells revealed both transcriptional upregulation of interferon stimulated genes (ISGs) and increased chromatin accessibility and occupancy of STAT and IRF factors, indicating augmented interferon signaling and sensitivity. Results Exposure to interferon gamma (IFNg) alone resulted in a durable increase in metastatic burden both in naïve and tumor experienced mice but not in immunodeficient hosts. Individual metastatic foci from IFNg treated cells were similarly sized to those from untreated cells and neither obtained a proliferative advantage, nor maintained significantly higher PD-L1 or MHC-I expression. Antibody depletion studies showed that the IFNg mediated evasion was through escape of NK cell interactions. Specifically, these interactions occurred within the first day of metastatic seeding and were mediated by the upregulation of both canonic and novel ISGs Conclusion Combined, these data reveal a possible mechanism by which patients with partial responses to immunotherapy undergo metastatic recurrence and highlight the need for close monitoring of these patients for metastatic spread.