Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade

By S. Wei, Jacob H. Levine, Alexandria P. Cogdill, Yang Zhao, Nana-Ama A S Anang, M. Andrews, Padmanee Sharma, Jing Wang, J. Wargo, Dana Pe'er and 1 more. Cell, 2017

1,153 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/a7cb4cd72417cf6e413dc48d3a6207de8b6bb33c

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Citations in the corpus

Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma (2020, background): “CD4 exhausted T cells expressed follicular helper-associated molecules ICOS and CXCL13 (Figures 4D and S4B), resembling cells shown to mediate responses to CTLA-4 blockade (Wei et al., 2017).”
Tumor Mutation Burden and Efficacy of Nivolumab Monotherapy and in Combination With Ipilimumab in Small Cell Lung Cancer (2018, neutral): “Further work is needed to fully understand the precise immunobiologic mechanisms underlying synergy between PD-1 and CTLA-4 blockade (Wei et al., 2017).”
Mechanisms of resistance to immune checkpoint inhibitors (2018, background): “…T cells using mass cytometry revealed distinct mechanisms of action of PD-1 and CTLA-4 blockade, demonstrating that PD-1 blockade reinvigorates CD8þ T-cell responses, and CTLA-4 blockade results in the expansion of Th1-like CD4þ cells expressing the co-stimulatory ligand ICOS (Wei et al, 2017).”
Distinct Immune Cell Populations Define Response to Anti-PD-1 Monotherapy and Anti-PD-1/Anti-CTLA-4 Combined Therapy. (2019, positive): “Data are emerging that combination immunotherapy and anti-PD-1 monotherapy act upon different populations of immune cells at different stages of immune activation, with PD-1 inhibition promoting clonal expansion of previously activated, functionally impaired cytotoxic T cells (Inozume et al., 2010; ”