Journal
JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 10, Issue 9, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2022-004585
Keywords
immunity; tumor microenvironment
Categories
Funding
- National Natural Science Foundation of China [82172689, 81972869, 31729001, 81902386]
- National Key RD Program [2018YFC1313400]
- Key R&D Project of Science and Technology Department of Jiangsu Province [BE2022721, BE2022719]
- China Postdoctoral Science Foundation [2021M700543, 2021M700547]
- High-Level Talents Project of Jiangsu Commission of Health [LGY2020034]
- Changzhou International Cooperation Project [CZ20210035]
Ask authors/readers for more resources
This study reveals the critical role of IL1 signaling in inhibiting Treg-mediated tumor immune suppression by modulating the interaction between Tregs and CAFs. These findings provide a theoretical basis for developing new anti-tumor immunotherapy strategies.
Background Regulatory T cells (Treg) are an integral part of the tumor immune tolerance. Carcinoma-associated fibroblasts (CAFs) is a pivotal driver for accumulation of Treg cells in the tumor microenvironment (TME). The molecular nature underpinning Treg cells and CAFs coupling needs to be further defined. Methods The Il1r2(flox/flox)Foxp3(Cre) mice were generated to establish the conditional knock-out of Il1r2 in Foxp3(+) Tregs in vivo. Using the MC38 tumor model, we evaluated the antitumor efficacy of immune checkpoint inhibitors (ICIs) and further analyzed the immune profiling of the TME by multicolor flow cytometry. Single-cell RNA sequencing of the whole tumor tissues, TCR repertoire analysis of sorted CD3(+) TILs were also performed. Results We showed that IL1 receptor 2 (IL1R2), a decoy receptor that neutralizes IL1, was highly expressed in Treg cells in the TME. In addition, we found that Il1r1 was largely expressed in the CAFs, suggesting IL1R2 plays a role in modulating crosstalk between Tregs and CAFs. We further demonstrated that Il1r2 deficiency in Treg cells led to greater antitumor efficacy of ICI, decreased Tregs and increased CD8(+) T cells in the TME, as well as reduced levels of T cell dysfunction. Mechanistically, we showed that IL1 inhibited major histocompatibility complex class II (MHC-II) expression on fibroblasts and Treg-specific Il1r2 deletion led to a decrease in genes associated with MHC-II antigen presentation in CAFs. Conclusions Our study established a critical role of IL1 signaling in inhibiting Treg-mediated tumor immune suppression through downregulating MHC-II antigen presentation in CAFs.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available