Human breast tumor-infiltrating CD8+ T cells retain polyfunctionality despite PD-1 expression

Colt A Egelston,Travis Y Tu,Laleh Melstrom,Kim Margolin,Laura Kruper,Diana L Simons,John H Yim,Peter P Lee,Joanne Mortimer,Jae Y Jung,Christian Avalos,Grecia Jimenez

doi:10.1038/s41467-018-06653-9

Colt A Egelston, Travis Y Tu + Show 10 more

Open Access

https://doi.org/10.1038/s41467-018-06653-9

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Abstract

Functional CD8+ T cells in human tumors play a clear role in clinical prognosis and response to immunotherapeutic interventions. PD-1 expression in T cells involved in chronic infections and tumors such as melanoma often correlates with a state of T-cell exhaustion. Here we interrogate CD8+ tumor-infiltrating lymphocytes (TILs) from human breast and melanoma tumors to explore their functional state. Despite expression of exhaustion hallmarks, such as PD-1 expression, human breast tumor CD8+ TILs retain robust capacity for production of effector cytokines and degranulation capacity. In contrast, melanoma CD8+ TILs display dramatic reduction of cytokine production and degranulation capacity. We show that CD8+ TILs from human breast tumors can potently kill cancer cells via bi-specific antibodies. Our data demonstrate that CD8+ TILs in human breast tumors retain polyfunctionality, despite PD-1 expression, and suggest that they may be harnessed for effective immunotherapies.

Highlights

Functional CD8+ T cells in human tumors play a clear role in clinical prognosis and response to immunotherapeutic interventions
Cells were identified as naive (CCR7+ CD45RA+), central memory (CM, CCR7+ CD45RA−), effector memory (EM, CCR7− CD45RA−), or effector memory RA+ (EMRA, CCR7− CD45RA+) (Fig. 1a). bcTumor and melTumor CD8+ tumor-infiltrating lymphocytes (TILs) were both primarily composed of EM cells (Fig. 1b)
In this study, we show that CD8+ TILs in human breast tumors are predominantly of effector memory phenotype, express checkpoint molecules PD-1, TIGIT, and 2B4, and are enriched for PD-1+ Eomes+ T-bet− cells

Summary

Introduction

Functional CD8+ T cells in human tumors play a clear role in clinical prognosis and response to immunotherapeutic interventions. CD8+ T cells can exert effector function through their capacity to recognize and kill tumor targets[8,9] Despite their tumor cytolytic capacity, CD8+ tumor-infiltrating lymphocytes (TILs) may lose their functional potential in the presence of chronic antigen undergoing a state known as T-cell exhaustion[10]. Tumor antigen-specific CD8+ T cells with severely reduced function have been described in melanoma patients[16,17] In both chronic infections and cancer, exhausted CD8+ T cells have been shown to upregulate the expression of the checkpoint molecule programmed cell death protein 1 (PD-1), which has largely been viewed as a surrogate marker of T-cell exhaustion[18,19,20,21,22]. While a CD127− KLRG1− phenotype is found on early effector cells after initial antigen exposure, it is found on severely exhausted terminal effector cells resulting from chronic antigen exposure[37,38]

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