[PDF][PDF] Non-conventional inhibitory CD4+ Foxp3− PD-1hi T cells as a biomarker of immune checkpoint blockade activity

R Zappasodi, S Budhu, MD Hellmann, MA Postow… - Cancer cell, 2018 - cell.com
Cancer cell, 2018cell.com
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 (4PD1 hi) and observed that 4PD1 hi
accumulate intratumorally as a function of tumor burden. Interestingly, CTLA-4 blockade
promotes intratumoral and peripheral 4PD1 hi increases in a dose-dependent manner,
while combination with PD-1 blockade mitigates this effect and improves anti-tumor activity …
Summary
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.
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