Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy

By S. Im, M. Hashimoto, Michael Y. Gerner, JungHwa Lee, H. Kissick, Matheus C. Bürger, Q. Shan, J. Hale, Judong Lee, T. Nasti and 6 more. Nature, 2016

1,792 citations recorded by the source corpus.

Chronic viral infections are characterized by a state of CD8+ T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8+ T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8+ T cells. Here we identify a population of virus-specific CD8+ T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8+ T cells expressed the PD-1 inhibitory receptor, but also expressed several costimulatory molecules such as ICOS and CD28. This CD8+ T-cell subset was characterized by a unique gene signature that was related to that of CD4+ T follicular helper (TFH) cells, CD8+ T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4+ TH1 cells and CD8+ terminal effectors. This CD8+ T-cell population was found only in lymphoid tissues and resided predominantly in the T-cell zones along with naive CD8+ T cells. These PD-1+CD8+ T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8+ T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8+ T-cell subset. Notably, the transcription factor TCF1 had a cell-intrinsic and essential role in the generation of this CD8+ T-cell subset. These findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/11108e8157d13261889dbc90a8f8805f766d986d

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Citations in the corpus

Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade (2016, neutral): “In particular, the TEX population appears heterogeneous in TCIR expression, exhaustion-related markers, and reinvigoration potential (Blackburn et al., 2008; He et al., 2016; Im et al., 2016; Utzschneider et al., 2016).”
Systemic Immunity is Required for Effective Cancer Immunotherapy (2017, neutral): “Many studies have focused on CD8 T cells (Chen and Mellman, 2013; Im et al., 2016), with less emphasis on harnessing CD4 T cells (Tran et al.”
T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition (2016, background): “Indeed, recent LCMV experiments have implicated an early memory population as being the targets for expansion by anti-PD-L1/PD-1 (44, 45).”
Defining T cell states associated with response to checkpoint immunotherapy in melanoma (2018, neutral): “These findings are consistent with a recent study showing that loss of TCF7 expression is associated with acquisition of effector phenotype in response to anti-PD-1 treatment in a mouse model of LCMV infection (Im et al., 2016).”
Pan-cancer single-cell landscape of tumor-infiltrating T cells (2021, background): “It has been hypothesized that the progenitor cells that express CXCR5 or TCF7 give rise to terminal Tex cells (23, 32, 33).”
T follicular helper cell biology: A decade of discovery and diseases (2019, background): “…exclusive, but it has become clear that CD8+ T cells can appropriate Tfh cell-associated gene expression in a TCF1- and Id2dependent manner to express CXCR5 and other Tfh cell-associated genes, and it is those CXCR5+ CD8+ T cells that respond most robustly to PD1 immunotherapy (Im et al., 2016).”
Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade (2017, neutral): “It is possible that expansion of specific tumor-infiltrating T cell subsets in response to ICB results from engagement of distinct progenitor populations in secondary lymphoid organs, analogous to findings in viral models (Im et al., 2016).”