Estrogen Receptor signaling drives immune evasion and immunotherapy resistance in HR+ breast cancer

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Abstract

Hormone Receptor positive (HR+) breast cancers (BC) are typically “immune-cold” poorly immune infiltrated tumors that do not respond to immune-checkpoint blockade (ICB) therapies. Using clinical data, we report that estrogen receptor (ERα) signaling associates with immunosuppressive pathways and lack of response to ICB in HR+ patients. In this study, we validate ER-mediated immunosuppression by engineering and modulating ER in preclinical models in vitro, in vivo and ex vivo. Mechanistically, we found that ERα hijacks LCOR, a nuclear receptor corepressor, thereby preventing LCOR’s function in the induction of tumor immunogenicity and immune infiltration, which is normally observed in the absence of ERα, such as in ER-negative BC. In HR+BC, we demonstrate that the molecular disruption of LCOR and ERα interaction using anti-ER therapies or using a mutant of the LCOR nuclear-receptor binding domain (LSKLL into LSKAA) that does not interact with ERα, restores LCOR’s immunogenic functions. Remarkably, the LCOR-ERα disruption converts HR+BC immune-cold tumors into immune-hot tumors responsive to ICB by increased antigen presentation machinery (APM) expression, immune infiltration, T cell recognition and mediated killing. In conclusion, ERα inhibition and the disruption of LCOR to ERα represent a novel therapeutic strategy and an opportunity to elicit immunotherapeutic benefit in HR+BC patients.

Authors

José Ángel Palomeque, Gabriel Serra-Mir, Sandra Blasco-Benito, Helena Brunel, Pau Torren-Duran, Iván Pérez-Núñez, Chiara Cannatá, Laura Comerma, Silvia Menendez, Sonia Servitja, Tamara Martos, Maria Castro, Rodrigo L. Borges, Joanna I. Lopez-Velazco, Sara Manzano, Santiago Duro-Sánchez, Joaquin Arribas, Maria M. Caffarel, Ander Urruticoechea, Jose A. Seoane, Lluis Morey, Joan Albanell, Toni Celià-Terrassa