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

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 (T-Ex). Tumors with abundant CD8(+)T(Ex) exhibited a distinct tumor microenvironment marked by amplified interferon-gamma signaling-related pathways and higher programmed death ligand 1 expression. Paradoxically, higher levels of tumor-infiltrating CD8(+)T(Ex) associated with decreased overall survival of patients with ER+ BC but not patients with TNBC. Moreover, high tumor expression of a CD8(+)T(Ex) signature identified dramatically reduced survival in premenopausal, but not postmenopausal, patients with ER+ BC. Finally, we demonstrated the value of a tumor T-Ex 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-gamma signaling, and ER status in BC patient survival. This work identifies tumor-infiltrating CD8(+)T(Ex) as a key feature of reduced survival outcomes in premenopausal patients with early-stage ER+ BC.