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

Abstract

Recruitment of regulatory T cells (T_regs) to tumors is a hallmark of cancer progression. Tumor-derived factors, such as the cytokine thymic stromal lymphopoietin (TSLP), can influence T_reg function in tumors. In our study, we identified a subset of T_regs expressing the receptor for TSLP (TSLPR⁺ T_regs) that were increased in colorectal tumors in humans and mice and largely absent in adjacent normal colon. This T_reg 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 T_reg 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. T_reg-specific deletion of TSLPR, but not ST2, was associated with a reduction in tumor number and size with concomitant increase in T_H1 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 T_reg function and represents a potential therapeutic target that requires further investigation.