Cell
Volume 170, Issue 6, 7 September 2017, Pages 1120-1133.e17
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Article
Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade

https://doi.org/10.1016/j.cell.2017.07.024Get rights and content
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Highlights

  • Anti-PD-1 and anti-CTLA-4 utilize distinct cellular mechanisms

  • T cell responses to different tumor models are fundamentally similar

  • Anti-PD-1 and anti-CTLA-4 both target subsets of exhausted-like CD8 T cells

  • CTLA-4 blockade induces expansion of ICOS+ Th1-like CD4 T cells

Summary

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.

Keywords

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

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