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

BC Miller, DR Sen, R Al Abosy, K Bi, YV Virkud… - Nature …, 2019 - nature.com
BC Miller, DR Sen, R Al Abosy, K Bi, YV Virkud, MW LaFleur, KB Yates, A Lako, K Felt…
Nature immunology, 2019nature.com
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 …
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.
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