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

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...

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Bibliographic Details
Published in:Cell 2017-09, Vol.170 (6), p.1120-1133.e17
Main Authors: Wei, Spencer C., Levine, Jacob H., Cogdill, Alexandria P., Zhao, Yang, Anang, Nana-Ama A.S., Andrews, Miles C., Sharma, Padmanee, Wang, Jing, Wargo, Jennifer A., Pe’er, Dana, Allison, James P.
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Language:English
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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. [Display omitted] •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 Anti-CTLA-4 and anti-PD-1 checkpoint-blockade therapies target distinct tumor-infiltrating T cell populations to induce tumor rejection.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2017.07.024