Amphiregulin couples IL1RL1 + regulatory T cells and cancer-associated fibroblasts to impede antitumor immunity.

Regulatory T (T reg ) cells and cancer-associated fibroblasts (CAFs) jointly promote tumor immune tolerance and tumorigenesis. The molecular apparatus that drives T reg cell and CAF coordination in the tumor microenvironment (TME) remains elusive. Interleukin 33 (IL-33) has been shown to enhance fibrosis and IL1RL1 + T reg cell accumulation during tumorigenesis and tissue repair. We demonstrated that IL1RL1 signaling in T reg cells greatly dampened the antitumor activity of both IL-33 and PD-1 blockade. Whole tumor single-cell RNA sequencing (scRNA-seq) analysis and blockade experiments revealed that the amphiregulin (AREG)-epidermal growth factor receptor (EGFR) axis mediated cross-talk between IL1RL1 + T reg cells and CAFs. We further demonstrated that the AREG/EGFR axis enables T reg cells to promote a profibrotic and immunosuppressive functional state of CAFs. Moreover, AREG mAbs and IL-33 concertedly inhibited tumor growth. Our study reveals a previously unidentified AREG/EGFR-mediated T reg /CAF coupling that controls the bifurcation of fibroblast functional states and is a critical barrier for cancer immunotherapy.