CD8+ T cells in the tumor microenvironment modulate response to endocrine therapy in breast cancer

The role of the tumor immune microenvironment (TIME) in modulating responses to antiestrogen therapy in hormone receptor-positive (HR+) breast cancers remains unclear. We analyzed pre- and on-treatment biopsies from patients with HR+ breast cancer treated with letrozole to induce estrogen deprivation (ED). Stromal tumor-infiltrating lymphocytes, assessed by H&E-staining, and immune-related gene sets, including IFNɣ signaling, measured by RNA sequencing, were increased in ED-resistant tumors. Cyclic immunofluorescence and spatial transcriptomics revealed an abundance of CD8+ T cells and enhanced antigen processing and immune gene signatures in ED-resistant tumors. In this group, the expression of CXCL9, CXCL10, and CXCL11 - chemokine genes involved in CD8+ T cell recruitment - and the CXCR3 receptor were upregulated both before and after letrozole. CXCL11 levels were higher in conditioned media from HR+ breast cancer cells co-cultured with CD8+ T cells. Both recombinant CXCL11 and co-culture with CD8+ T cells promoted MCF7 and T47D cell growth in estrogen-free conditions. Finally, deletion combined with silencing of the CXCL11 receptors CXCR3 and CXCR7 in MCF7 cells impaired proliferation in response to exogenous CXCL11 and to co-culture with CD8+ T cells in estrogen-free conditions. These findings suggest that CD8+ T cell-associated CXCL11 in the TIME modulates the response of HR+ breast cancer cells to estrogen suppression.