Emerging role for thymic stromal lymphopoietin–responsive regulatory T cells in colorectal cancer progression in humans and mice

Recruitment of regulatory T cells (Tregs) to tumors is a hallmark of cancer progression. Tumor-derived factors, such as the cytokine thymic stromal lymphopoietin (TSLP), can influence Treg function in tumors. In our study, we identified a subset of Tregs expressing the receptor for TSLP (TSLPR+ Tregs) that were increased in colorectal tumors in humans and mice and largely absent in adjacent normal colon. This Treg subset was also found in the peripheral blood of patients with colon cancer but not in the peripheral blood of healthy control subjects. Mechanistically, we found that this Treg subset coexpressed the interleukin-33 (IL-33) receptor [suppressor of tumorigenicity 2 (ST2)] and had high programmed cell death 1 (PD-1) and cytotoxic lymphocyte-associated antigen 4 (CTLA-4) expression, regulated in part by the transcription factor Mef2c. Treg-specific deletion of TSLPR, but not ST2, was associated with a reduction in tumor number and size with concomitant increase in TH1 cells in tumors in chemically induced mouse models of colorectal cancer. Therapeutic blockade of TSLP using TSLP-specific monoclonal antibodies effectively inhibited the progression of colorectal tumors in this mouse model. Collectively, these data suggest that TSLP controls the progression of colorectal cancer through regulation of tumor-specific Treg function and represents a potential therapeutic target that requires further investigation.