| Literature DB >> 29894689 |
Roberta Zappasodi1, Sadna Budhu2, Matthew D Hellmann3, Michael A Postow4, Yasin Senbabaoglu2, Sasikanth Manne5, Billel Gasmi2, Cailian Liu2, Hong Zhong2, Yanyun Li2, Alexander C Huang6, Daniel Hirschhorn-Cymerman2, Katherine S Panageas7, E John Wherry6, Taha Merghoub8, Jedd D Wolchok9.
Abstract
A significant proportion of cancer patients do not respond to immune checkpoint blockade. To better understand the molecular mechanisms underlying these treatments, we explored the role of CD4+Foxp3- T cells expressing PD-1 (4PD1hi) and observed that 4PD1hi accumulate intratumorally as a function of tumor burden. Interestingly, CTLA-4 blockade promotes intratumoral and peripheral 4PD1hi increases in a dose-dependent manner, while combination with PD-1 blockade mitigates this effect and improves anti-tumor activity. We found that lack of effective 4PD1hi reduction after anti-PD-1 correlates with poor prognosis. Mechanistically, we provide evidence that mouse and human circulating and intra-tumor 4PD1hi inhibit T cell functions in a PD-1/PD-L1 dependent fashion and resemble follicular helper T cell (TFH)-like cells. Accordingly, anti-CTLA-4 activity is improved in TFH deficient mice.Entities:
Keywords: CD4(+) T cells; CTLA-4; PD-1; PD-L1; cancer immunotherapy; follicular helper T cells; immune checkpoint blockade; immune resistance; immune tolerance; regulatory T cells
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Year: 2018 PMID： 29894689 PMCID： PMC6648657 DOI： 10.1016/j.ccell.2018.05.009
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743