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.