Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1 CD8 + Tumor-Infiltrating T Cells

Sema Kurtulus, Asaf Madi, Giulia Escobar, Max Klapholz, Jackson Nyman, Elena Christian, Mathias Pawlak, Danielle Dionne, Junrong Xia, Orit Rozenblatt-Rosen, Vijay K. Kuchroo, Aviv Regev, Ana C. Anderson

Research output: Contribution to journalArticlepeer-review

Abstract

An improved understanding of the anti-tumor CD8 + T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effector response of CD8 + tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8 + TILs after combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1 TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effector capacity, and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8 + T cells associated with response to checkpoint blockade in patients and was compromised in the absence of Tcf7. Expression of Tcf7/Tcf1 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8 + T cell responses upon immunotherapy.

Original languageEnglish
Pages (from-to)181-194.e6
JournalImmunity
Volume50
Issue number1
DOIs
StatePublished - 15 Jan 2019

Keywords

  • CD8 T cell
  • PD-1
  • Tim-3
  • cancer
  • checkpoint blockade
  • dysfunction
  • exhaustion
  • immunotherapy
  • memory
  • single-cell

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