Non-conventional Inhibitory CD4+Foxp3−PD-1hi T Cells as a Biomarker of Immune Checkpoint Blockade Activity

Publication date: 11 June 2018
Source:Cancer Cell, Volume 33, Issue 6
Author(s): Roberta Zappasodi, Sadna Budhu, Matthew D. Hellmann, Michael A. Postow, Yasin Senbabaoglu, Sasikanth Manne, Billel Gasmi, Cailian Liu, Hong Zhong, Yanyun Li, Alexander C. Huang, Daniel Hirschhorn-Cymerman, Katherine S. Panageas, E. John Wherry, Taha Merghoub, Jedd D. Wolchok
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. We found that lack of effective 4PD1^hi reduction after anti-PD-1 correlates with poor prognosis. Mechanistically, we provide evidence that mouse and human circulating and intra-tumor 4PD1^hi 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.

Graphical abstract

Teaser

Zappasodi et al. show that a subset of CD4⁺Foxp3⁻ T cells with high PD-1 expression, designated 4PD1^hi cells, inhibits T cell functions. CTLA-4 blockade increases intratumoral and systemic 4PD1^hi cells, while combination with PD-1 blockade reduces the increase of 4PD1^hi cells and improves anti-tumor activity.


https://ift.tt/2HFVBMs