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

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Abstract

Hormone receptor–positive (HR+) breast cancers (BCs) 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 α (ERα) signaling was associated with immunosuppressive pathways and a lack of response to ICB in patients with HR+ BC. In this study, we validated ER-mediated immunosuppression by engineering and modulating the ER in preclinical models in vitro, in vivo, and ex vivo. Mechanistically, we found that ERα hijacked 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– 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, restored the immunogenic functions of LCOR. Remarkably, the LCOR-ERα disruption converted HR+ BC immune-cold tumors into immune-hot tumors responsive to ICB by increased antigen presentation machinery expression, immune infiltration, T cell recognition, and T cell–mediated killing. In conclusion, ERα inhibition and the disruption of LCOR-ERα interaction represent a therapeutic strategy and an opportunity to elicit immunotherapeutic benefit in patients with HR+ BC.

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. López-Velazco, Sara Manzano, Santiago Duro-Sánchez, Joaquín Arribas, María M. Caffarel, Ander Urruticoechea, José A. Seoane, Lluis Morey, Joan Albanell, Toni Celià-Terrassa