Opposing functions of distinct regulatory T cell subsets in colorectal cancer

Enrichment of regulatory T (Treg) cells in solid organ cancers is generally associated with poor prognosis; however, colorectal cancer (CRC) stands out as a notable exception. Here, we examined the heterogeneity of tumoral Treg cells in CRC and identified two distinct tumoral Treg subsets with differential Il10 expression. Selective depletion of interleukin-10-expressing (IL-10⁺) Treg cells promoted tumor growth by lifting the restraint on IL-17 production from effector CD4⁺ T cells, thereby directly stimulating tumor cell proliferation; depletion of IL-10^- Treg cells led to pronounced tumor regression. In human CRC, IL-10⁺ and IL-10^- Treg abundance correlated with favorable and unfavorable prognosis, respectively. Accordingly, IL-10⁺ and IL-10^- Treg cells exhibited opposite enrichment patterns in adjacent normal colon tissues and tumors. Transcriptionally similar Treg subsets were observed across different human barrier tissue tumors. This functional dichotomy between Treg subsets may enable selective targeting of the pro-tumoral subset while preserving its anti-tumoral counterpart in CRC and other barrier tissue cancers.