Checkpoint inhibitors create rogue regulatory T cells
Smriti Parashar, Klaus Ley
Smriti Parashar, Klaus Ley
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Commentary

Checkpoint inhibitors create rogue regulatory T cells

Abstract

Immune checkpoint inhibitor–induced inflammatory arthritis (ICI-IA) is an immune-related adverse event (irAE) following treatment with PD-1, PD-L1, or CTLA-4 inhibitors in patients with cancer. In this issue of the JCI, Ma and colleagues identified a subset of regulatory T cells (Tregs) that coexpress CD137 and IL-6 receptor (IL6R), termed atypical Tregs (AtpTregs), which are selectively enriched in patients with ICI-IA. Functionally, AtpTregs exhibited reduced suppressive capacity and a Th17-like proinflammatory phenotype. Notably, these cells were associated with more severe arthritis, yet improved cancer outcomes, suggesting a potential role in tumor control. The anti-IL6R therapy tocilizumab, administered as an off-label intervention for ICI-IA, reduced AtpTreg abundance and alleviated arthritis while maintaining antitumor immunity in a small cohort of patients with new-onset ICI-IA. Thus, anti-IL6R could be a targeted approach to manage ICI-IA and potentially other irAEs involving AtpTregs.

Authors

Smriti Parashar, Klaus Ley

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Figure 1

ICI-IA is associated with emergence of atypical Tregs that are sensitive to IL6R inhibitors.

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ICI-IA is associated with emergence of atypical Tregs that are sensitive...
(A) Ma et al. (4) showed that a distinct subset of atypical regulatory T cells (AtpTregs, tan) is enriched in patients treated with immune checkpoint inhibitors (ICIs) who developed ICI-induced inflammatory arthritis (ICI-IA). These AtpTregs retained the expression of classic Treg (blue) markers like CD25 and FOXP3 and were identified by the surface expression of CD137 and IL6 receptor (IL6RA). AtpTregs lost suppressive function and lost Treg markers like CTLA4, CD73, and LAG3. Instead, they gained the Th17-lineage markers RORC and IL17A. AtpTregs were cytotoxic and expressed granzyme B (GZMB). (B) Treatment of patients with ICI-IA with the anti-IL6R mAb tocilizumab reduced the number of AtpTregs and improved arthritis outcomes.