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

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

doi:10.1172/jci.insight.153963

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.

Highlights

In most cancer types, presence of tumor-infiltrating lymphocytes (TILs) denotes reduced risk for relapse and increased overall survival [1]
We examined breast cancer (BC) patient peripheral blood mononuclear cells (PBMCs), tumor-negative tumor-draining lymph nodes (T– LNs), tumor-positive tumor-draining lymph nodes (T+ LNs), primary tumors, and noncancerous breast tissue (NCBT) by flow cytometry for the presence of CD8+ T cells expressing T cell exhaustion markers programmed death 1 (PD-1) and CD39 (Figure 1A; gating strategy in Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.153963DS1)
Among antigen-experienced (CD45RA–) CD8+ T cells, PD-1+ cells were common in all tissues, but frequencies of PD-1+CD39+CD8+ T cells were highest in primary tumors, followed by T+ LNs (Figure 1B)

Summary

Introduction

Presence of tumor-infiltrating lymphocytes (TILs) denotes reduced risk for relapse and increased overall survival [1]. The prognostic impact of CD8+ TILs appears to be subtype specific in breast cancer (BC) [2, 3]. CD8+ tumor-infiltrating T cells positively associate with survival in triple-negative BC (TNBC) and human epidermal growth factor receptor 2 (HER2/neu) overexpressed (HER2+) BC, but not in estrogen receptor–positive (ER+) BC [4,5,6]. This paradox is further complicated by differences in kinetics of disease progression among BC subtypes. A better understanding of the relationship between TILs and patient outcomes is needed to guide therapeutic strategies for patients with ER+ BC, who compose approximately 70% of all patients with BC [8]

Methods

Results

Conclusion