Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade

Spencer C. Wei, Jacob H. Levine, Alexandria P. Cogdill, Yang Zhao, Nana Ama A.S. Anang, Miles C. Andrews, Padmanee Sharma, Jing Wang, Jennifer A. Wargo, Dana Pe'er, James P. Allison

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381 Citations (Scopus)

Abstract

Immune-checkpoint blockade is able to achieve durable responses in a subset of patients; however, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced tumor rejection. To address these issues, we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor-infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor-infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint-blockade-induced immune responses are driven by distinct cellular mechanisms.

Original languageEnglish
Pages (from-to)1120-1133.e17
Number of pages31
JournalCell
Volume170
Issue number6
DOIs
Publication statusPublished - 7 Sep 2017
Externally publishedYes

Keywords

  • checkpoint blockade
  • costimulation
  • CTLA-4
  • host immune response
  • mass cytometry
  • melanoma
  • PD-1
  • T cell
  • tumor
  • tumor-infiltrating lymphocyte

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