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

Cell | Sep 7, 2017

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.

Pubmed ID: 28803728 RIS Download

Mesh terms: Animals | CD8-Positive T-Lymphocytes | CTLA-4 Antigen | Disease Models, Animal | Female | Flow Cytometry | Gene Expression Regulation | Humans | Immunotherapy | Melanoma | Mice | Mice, Inbred C57BL | Neoplasm Metastasis | Programmed Cell Death 1 Receptor | Single-Cell Analysis | T-Lymphocyte Subsets | Transcription, Genetic

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA164729
  • Agency: NCI NIH HHS, Id: P30 CA016672
  • Agency: NCI NIH HHS, Id: R01 CA163793
  • Agency: NCI NIH HHS, Id: P30 CA008748
  • Agency: NICHD NIH HHS, Id: DP1 HD084071
  • Agency: NIGMS NIH HHS, Id: T32 GM008798
  • Agency: NCI NIH HHS, Id: K08 CA160692

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