Response to anti-PD-1 and anti-LAG-3 immune checkpoint blockade is associated with induction of pro-inflammatory Tregs.

Publication Title

AAI Annual Meeting; May 6-11; Portland, OR. 2022

Document Type

Abstract

Publication Date

5-2022

Keywords

oregon; chiles

Abstract

  1. Only a subset of patients exhibits durable clinical responses to aPD-1 and/or aCTLA-4 immunotherapies, thus, developing new therapeutic agents to increase the proportion of

responding patients is a priority. Combining aPD-1 with aLAG-3 has shown promising results;

however, lack of mechanistic understanding of aPD-1/aLAG-3 synergy remains a barrier for its

  • optimal clinical use. Here, we examined the mechanism of aPD-1/aLAG-3 synergy in multiple mouse models using flow cytometry and single cell RNA sequencing. Combined aPD-1/aLAG-3

immunotherapy significantly improved the survival of CT26 (BALB/c; colon carcinoma) and MCA-205 (C57BL/6; sarcoma) tumor-bearing mice compared to monotherapy. Regulatory T cells (Tregs) suppressed response to this therapy, as in the absence of CD4+ T cells, 100% of

mice responded. To understand how responders overcome Treg suppression, we performed an

in-depth analysis of tumor-infiltrating lymphocytes (TIL) comparing mice that responded to

treatment (decreased tumor size post-treatment) to non-responders (same tumor growth

trajectory as control). Responders had reduced Foxp3+ CD4+ Tregs in comparison to nonresponders and, in addition, those Tregs had a ‘fragile’ phenotype, including a pro-inflammatory cytokine profile (TNF-a; IFN-g), increased LAG-3, and decreased NRP1 expression. Within responders, CD8+ TIL exhibited increased frequency, effector cytokine production (TNF-a; IFNg), and LAG-3 expression as compared to non-responders. Together, these data suggest that aPD-1/aLAG-3 can reduce Treg frequency and function leading to expansion of active tumor specific CD8+ T cells capable of supporting tumor regression and improved survival

Area of Special Interest

Cancer

Specialty/Research Institute

Earle A. Chiles Research Institute

Specialty/Research Institute

Oncology

Comments

Rolig AS, Sturgill ER, Mick C, Rose D, Kaufmann J, Yanamandran N, Griffin S, Smothers J, Redmond WL. AAI Annual Meeting; May 6-11; Portland, OR. 2022: P933.

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