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- W4313359567 abstract "Abstract A significant proportion of cancer patients do not respond to immune checkpoint blockade therapy. To deepen our understanding of the mechanisms of resistance to immunotherapy, we studied a population of CD4+Foxp3− T cells expressing PD-1 (4PD1hi), which we found to be up-regulated in B16-melanoma bearing mice after CTLA-4 blockade in association with limited response to treatment. We observed that 4PD1hi accumulate intratumorally as a function of tumor burden in untreated tumor-bearing hosts. Interestingly, CTLA-4 blockade promotes intratumoral and peripheral 4PD1hiincreases in a dose-dependent manner, while combination with PD-1 blockade mitigates this effect in both B16-bearing mice and melanoma patients and significantly improves anti-tumor activity. In addition, we found that persistence of high levels of 4PD1hi after PD-1 blockade correlates with poor prognosis in melanoma patients. Mechanistically, we show that mouse and human circulating and intra-tumor 4PD1hi inhibit T-cell functions in a PD-1/PD-L1 dependent fashion. In addition, we found that mouse and human 4PD1hi resemble follicular-helper-T-cell(TFH)-like cells and that CTLA-4 blockade activity is improved in TFH deficient mice. These findings broaden our understanding of the mechanisms that limit anti-tumor immunity, providing an additional explanation for the incremental activity of combined CTLA-4 and PD-1 blockade. Our study also defines 4PD1hi as a new prognostic and pharmacodynamic biomarker for the design of optimal checkpoint blockade combination schedules and dosage." @default.
- W4313359567 created "2023-01-06" @default.
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- W4313359567 date "2018-05-01" @default.
- W4313359567 modified "2023-09-27" @default.
- W4313359567 title "Modulation of TFH-like cells and anti-tumor activity of immune checkpoint blockade." @default.
- W4313359567 doi "https://doi.org/10.4049/jimmunol.200.supp.57.45" @default.
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