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

By Brian C. Miller, Debattama R. Sen, R. Abosy, K. Bi, Y. Virkud, M. LaFleur, Kathleen B. Yates, Ana Lako, K. Felt, G. S. Naik and 17 more. Nature Immunology, 2019

1,754 citations recorded by the source corpus.

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. Exhausted cytotoxic T lymphocytes (CTLs) express the receptor PD-1 as a key signature. Haining and colleagues show that there are different ‘depths’ of exhaustion with a subset of exhausted CTLs that retain polyfunctionality and are responsive to PD-1 blockade.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/0085cd68986038e14e6c930bd689674790e99fc6

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Citations in the corpus

Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity (2020, background): “CD8+ T cells were further characterized as proliferating, Tim3+ cytotoxic, or Slamf6+ stem cell-progenitor subsets based on the expression of the corresponding cell signature (Figures S3O– S3R; Kowalczyk et al., 2015; Miller et al., 2019).”
Tumor-infiltrating lymphocytes in the immunotherapy era (2020, background): “Taken together, these findings suggest that signature genes consistent with TPE cells may serve as a potential biomarker for ICB response.(57,58,60,63,64) In addition to the role of CD8 T cells and MHC class I, Elspach et al.”
Pan-cancer single-cell landscape of tumor-infiltrating T cells (2021, background): “Intrinsically, T cell exhaustion appears to be tightly regulated by several transcription factors (TFs), including TOX (thymocyte selection-associated high mobility group box) (4, 5) and TCF7 (transcription factor 7) (6), as well as epigenetic regulators that shape the specific state observed in dys”
Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment (2023, neutral): “4 While the blockade of inhibitory T cell receptors, such as programmed cell death-1 (PD-1) or its ligand PD-L1, unleashes antitumor T cell responses 5,6 and displays potent clinical efﬁcacy, only 40% of melanoma patients respond to treat-ment.”
Acquired Resistance to Immune Checkpoint Inhibitors (2020, background): “compared single-cell expression profiles from TIL CD8+ T cells in murine models of LCMV chronic infections versus tumors to further characterize T cell exhaustion (Miller et al., 2019).”