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Cell. 2017 Sep 7;170(6):1120-1133.e17. doi: 10.1016/j.cell.2017.07.024. Epub 2017 Aug 10.

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

Author information

1
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: scwei@mdanderson.org.
2
Computational and Systems Biology Program, Sloan Kettering Institute, New York, NY 10065, USA.
3
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
7
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
8
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
9
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: jallison@mdanderson.org.

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.

KEYWORDS:

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

PMID:
28803728
PMCID:
PMC5591072
DOI:
10.1016/j.cell.2017.07.024
[Indexed for MEDLINE]
Free PMC Article

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