IL1R2 increases regulatory T cell population in the tumor microenvironment by enhancing MHC-II expression on cancer-associated fibroblasts

Abstract

BackgroundRegulatory 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.MethodsThe Il1r2flox/floxFoxp3Cre 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.ResultsWe 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.ConclusionsOur study established a critical role of IL1 signaling in inhibiting Treg-mediated tumor immune suppression through downregulating MHC-II antigen presentation in CAFs.

Sex biased human thymic architecture guides T cell development through spatially defined niches

“…In addition to newly developing tTregs, the thymus also contains mature, highly activated Tregs, labeled as rrTregs, which are thought to have recirculated from the periphery 74,75 . These rrTregs do not express CCR7 or thymic egress markers (KLF2, S1PR1), but do express IL1R2 (Sup Figure 5F), a receptor known to sequester the inflammatory cytokine IL-1 to reduce local concentrations 76 . CODEX imaging identified tTregs and rrTregs dispersed throughout the medulla, with rrTregs primarily adjacent to DCs marked by CD68 expression (Figure 5G).…”

CAF-immune cell crosstalk and its impact in immunotherapy

“…A recent study shows evidence that Tregs can also modulate the phenotype of CAFs in an IL-1 signalling-dependent manner [ 59 ]. The authors show that IL-1R2, a decoy receptor for IL-1β, is exclusively expressed by tumour-infiltrating Tregs in several murine and human cancer types.…”

“…Inhibition of IL-1β signalling in CAFs results in increased expression of MHC-class II, indicating that the presence IL-1R2 + -Tregs in the TME can drive the differentiation of apCAFs, which the authors further describe, promoting the additional accumulation of Tregs. Supporting this, specific blockade of IL-1R2 in Tregs in their murine models improved anti-tumour immunity upon ICI therapy in several murine models [ 59 ].…”

TIGIT Blockade Reshapes the Tumor Microenvironment Based on the Single-cell RNA-Sequencing Analysis

“…3F, G and 4A). 31 FOXP3, a key transcription factor in Tregs, plays a crucial role in their differentiation, maturation, and in vivo inhibitory activity. 32,33 We found that the expression of Foxp3 was down-regulated after anti-TIGIT treatment (Fig.…”