Response to anti-PD-1 and anti-LAG-3 immune checkpoint blockade is associated with induction of pro-inflammatory Tregs.
AAI Annual Meeting; May 6-11; Portland, OR. 2022
- 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
Earle A. Chiles Research Institute
Rolig, AS; Redmond, William L.; and See full list of authors in comments, "Response to anti-PD-1 and anti-LAG-3 immune checkpoint blockade is associated with induction of pro-inflammatory Tregs." (2022). Articles, Abstracts, and Reports. 6112.