Journal
NATURE IMMUNOLOGY
Volume 20, Issue 3, Pages 326-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41590-019-0312-6
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Categories
Funding
- NIAID [R01 AI115712, U19 AI133524, P01 AI56299, K23 AI130408]
- Parker Institute for Cancer Immunotherapy
- Mathers Charitable Trust
- Ludwig Center at Harvard Medical School
- 2016 AACR-Bristol-Myers Squibb Fellowship in Translational Immuno-oncology grant [16-40-15-MILL]
- Wong Family Awards in Translational Oncology
- National Center for Advancing Translational Sciences/National Institutes of Health Award [KL2 TR002542]
- NCI [T32 CA009172, T32 CA207021]
- Jane C. Wright, MD, Endowed Young Investigator Award from ASCO
- NIGMS [T32 GM007753]
- NHLBI [T32 HL007627]
- Center for Immuno-Oncology at DFCI
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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.
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