Opposing functions of distinct regulatory T cell subsets in colorectal cancer

Regulatory T (Treg) cells are considered major contributors to the growth of solid organ tumors, with the notable exception of colorectal cancer (CRC), despite the documented abundance of Treg cells in CRC. Here, we demonstrate that IL-10⁺ and IL-10⁻ Treg cells constitute two distinct subsets with opposing functions: IL-10⁺ Treg cells counteract, while IL-10⁻ Treg cells promote, the growth of genetically engineered CRC tumors. Our findings suggest that the tumor-suppressive function of IL-10⁺ Treg cells is mediated by their suppression of effector CD4⁺ T cell production of IL-17, a cytokine that directly stimulates CRC tumor cell proliferation. Consistently, IL-10⁺ Treg cells were more abundant in both mouse and human CRC tumors than in tumor-adjacent normal colon tissue, whereas IL-10⁻ Treg cells exhibited the opposite distribution. Furthermore, gene expression signatures associated with IL-10⁺ and IL-10⁻ Treg cells correlated with better and worse disease prognoses in human CRC, respectively. This functional dichotomy between Treg subsets provides a rationale for therapeutic strategies aimed at selectively targeting pro-tumoral Treg cells while preserving their anti-tumoral counterparts across various barrier tissue cancers that harbor both subsets.