Faculty, Staff and Student Publications

Language

English

Publication Date

2-2-2026

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI188458

PMID

41364532

PMCID

PMC12867153

PubMedCentral® Posted Date

12-9-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Breast Neoplasms, Tumor Microenvironment, CD8-Positive T-Lymphocytes, Female, Letrozole, Lymphocytes, Tumor-Infiltrating, Receptors, CXCR3, MCF-7 Cells, Chemokine CXCL11, Neoplasm Proteins, Cell Line, Tumor, Antineoplastic Agents, Hormonal, Breast cancer, Chemokines, Drug therapy, Immunology, Oncology

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.