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

Brian C MillerDebattama R SenRose Al AbosyKevin BiYamini V VirkudMartin W LaFleurKathleen B YatesAna LakoKristen FeltGirish S NaikMichael ManosEvisa GjiniJuhi R KuchrooJeffrey J IshizukaJenna L CollierGabriel K GriffinSeth MaleriDawn E ComstockSarah A WeissFlavian D BrownArpit PandaMargaret D ZimmerRobert T MangusoF Stephen HodiScott J RodigArlene H SharpeW Nicholas Haining
Published in: Nature immunology (2019)
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.
Keyphrases
  • dna damage
  • induced apoptosis
  • dna methylation
  • stem cells
  • transcription factor
  • cell therapy
  • young adults
  • signaling pathway
  • heat shock
  • heat shock protein