CD8+ T cells in the tumor microenvironment modulate the 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 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.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-12-09
DOI
https://doi.org/10.1172/jci188458
Citations
1
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
1.05

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article

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

Pamela Luna, Shahbano Shakeel, Gordon Brent Mills, Ariella B. Hanker et al.
1 citations
Journal of Clinical Investigation
Cancer Immunotherapy and Biomarkers
1.05
article

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

Pamela Luna, Shahbano Shakeel, Gordon Brent Mills, Ariella B. Hanker, Paula I. González-Ericsson, Yuki Matsunaga, Carlos L. Arteaga, Kyung‐min Lee, Dhivya R. Sudhan, Marilyne Labrie, Saurabh Mendiratta, Lei Ming Guo, Luigi Formisano, Yasuaki Uemoto, Nisha G Unni, Alberto Servetto, Nathaniel Evans, Jeon Lee, Roberto Bianco, Yunguan Wang, Lin Xu, Spencer Barnes, Fabiana Napolitano, Justin Micah Balko, María del Rosario Chica-Parrado, Tao Wang, Hongli Ma, James Zhu, Chang-Ching Lin, Khushi Ahuja, Yisheng Fang
article en
1 citations

Abstract

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.

Journal of Clinical InvestigationVol. 136(3)
Cincinnati Children's Hospital Medical Center (US), Université de Sherbrooke (CA), Oregon Health & Science University (US), Vanderbilt University (US), Cancer Institute (WIA) (IN), Centre Hospitalier Universitaire de Sherbrooke (CA), Southwestern Medical Center (US), OHSU Knight Cancer Institute, Hanyang University (KR), University of Cincinnati (US), University of Naples Federico II (IT), The University of Texas Southwestern Medical Center (US), Vanderbilt University Medical Center (US)
U.S. Department of Defense, Susan G. Komen for the Cure, Breast Cancer Research Foundation, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, Sanofi, Cancer Prevention and Research Institute of Texas, University of Texas Southwestern Medical Center, Puma Biotechnology, National Institutes of Health, National Cancer Institute, Daiichi Sankyo Europe
Openalex Percentile: Top 15%
Cancer Immunotherapy and Biomarkers
1.05
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