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Nat Immunol. 2019 Mar;20(3):326-336. doi: 10.1038/s41590-019-0312-6. Epub 2019 Feb 18.

Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade.

Miller BC1,2,3,4,5, Sen DR1,3,6, Al Abosy R1,3, Bi K1,3, Virkud YV7, LaFleur MW1,3,4,5,6, Yates KB1,3, Lako A8, Felt K8, Naik GS8, Manos M2,8, Gjini E2,8, Kuchroo JR4,5,6, Ishizuka JJ1,2,3, Collier JL1,3,4,5,6, Griffin GK1,3,9, Maleri S4,5, Comstock DE1,3,6, Weiss SA1,3,6, Brown FD1,3,4,5,6, Panda A1,3, Zimmer MD3, Manguso RT3, Hodi FS2,8, Rodig SJ8,9, Sharpe AH3,4,5,6, Haining WN10,11,12.

Author information

1
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
3
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
5
Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
6
Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
7
Division of Pediatric Allergy and Immunology, Massachusetts General Hospital, Boston, MA, USA.
8
Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
9
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
10
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. wnhaining@gmail.com.
11
Broad Institute of MIT and Harvard, Cambridge, MA, USA. wnhaining@gmail.com.
12
Division of Medical Sciences, Harvard Medical School, Boston, MA, USA. wnhaining@gmail.com.

Abstract

T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8+ tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8+ TILs include a subpopulation of 'progenitor exhausted' cells that retain polyfunctionality, persist long term and differentiate into 'terminally exhausted' TILs. Consequently, progenitor exhausted CD8+ TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8+ T cells might be an important component of improving the response to checkpoint blockade.

PMID:
30778252
DOI:
10.1038/s41590-019-0312-6

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