Journal Article

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

Xu, Lin, Balko, Justin M., Wang, Tao, Labrie, Marilyne, Gonzalez-Ericsson, Paula I., Shakeel, Shahbano, Hanker, Ariella B., Wang, Yunguan, Arteaga, Carlos L., Evans, Nathaniel J., Mills, Gordon B., Lee, Jeon, Unni, Nisha, Lee, Kyung-Min, Ahuja, Khushi, Luna, Pamela, Formisano, Luigi, Guo, Lei, Ma, Hongli, Mendiratta, Saurabh, Bianco, Roberto, Chica-Parrado, María Rosario, Napolitano, Fabiana, Zhu, James Z., Fang, Yisheng V., Matsunaga, Yuki, Barnes, Spencer D., Sudhan, Dhivya R., Lin, Chang-Ching A., Uemoto, Yasuaki, Servetto, Alberto

2026

Overview

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 IFN-γ signaling genes, measured by RNA-Seq, 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 treatment. CXCL11 levels were higher in conditioned media from HR + breast cancer cells cocultured with CD8 + T cells. Both recombinant CXCL11 and coculture 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 coculture with CD8 + T cells in estrogen-free conditions. These findings suggest that CD8 + T cell–associated CXCL11 in the TIME modulated the response of HR + breast cancer cells to estrogen suppression.

• Publisher: American Society for Clinical Investigation
• Subject: Antineoplastic Agents, Hormonal - pharmacology / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - immunology / Breast Neoplasms - pathology / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - pathology / Cell Line, Tumor / Chemokine CXCL11 - genetics / Chemokine CXCL11 - immunology / Female / Humans / Letrozole - pharmacology / Lymphocytes, Tumor-Infiltrating - immunology / Lymphocytes, Tumor-Infiltrating - pathology / MCF-7 Cells / Neoplasm Proteins - genetics / Neoplasm Proteins - immunology / Receptors, CXCR3 - genetics / Receptors, CXCR3 - immunology / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology