Tumor-infiltrating exhausted CD8⁺ T cells dictate reduced survival in premenopausal estrogen receptor–positive breast cancer

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Abstract

CD8+ tumor-infiltrating lymphocytes (TILs) are associated with improved survival in triple-negative breast cancer (TNBC) yet have no association with survival in estrogen receptor–positive (ER+) BC. The basis for these contrasting findings remains elusive. We identified subsets of BC tumors infiltrated by CD8+ T cells with characteristic features of exhausted T cells (TEX). Tumors with abundant CD8+ TEX exhibited a distinct tumor microenvironment marked by amplified interferon-γ signaling–related pathways and higher programmed death ligand 1 expression. Paradoxically, higher levels of tumor-infiltrating CD8+ TEX associated with decreased overall survival of patients with ER+ BC but not patients with TNBC. Moreover, high tumor expression of a CD8+ TEX signature identified dramatically reduced survival in premenopausal, but not postmenopausal, patients with ER+ BC. Finally, we demonstrated the value of a tumor TEX signature score in identifying high-risk premenopausal ER+ BC patients among those with intermediate Oncotype DX Breast Recurrence Scores. Our data highlight the complex relationship between CD8+ TILs, interferon-γ signaling, and ER status in BC patient survival. This work identifies tumor-infiltrating CD8+ TEX as a key feature of reduced survival outcomes in premenopausal patients with early-stage ER+ BC.

Authors

Colt A. Egelston, Weihua Guo, Jiayi Tan, Christian Avalos, Diana L. Simons, Min Hui Lim, Yinghui J. Huang, Michael S. Nelson, Arnab Chowdhury, Daniel B. Schmolze, John H. Yim, Laura Kruper, Laleh Melstrom, Kim Margolin, Joanne E. Mortimer, Yuan Yuan, James R. Waisman, Peter P. Lee