CD4 + T cells that express the forkhead box P3 (FOXP3) transcription factor function as regulatory T (T reg) cells and hinder effective immune responses against cancer cells. Abundant T reg cell infiltration into tumors is associated with poor clinical outcomes in various types of cancers. However, the role of T reg cells is controversial in colorectal cancers (CRCs), in which FOXP3 + T cell infiltration indicated better prognosis in some studies. Here we show that CRCs, which are commonly infiltrated by suppression-competent FOXP3 hi T reg cells, can be classified into two types by the degree of additional infiltration of FOXP3 lo nonsuppressive T cells. The latter, which are distinguished from FOXP3 + T reg cells by non-expression of the naive T cell marker CD45RA and instability of FOXP3, secreted inflammatory cytokines. Indeed, CRCs with abundant infiltration of FOXP3 lo T cells showed significantly better prognosis than those with predominantly FOXP3 hi T reg cell infiltration. Development of such inflammatory FOXP3 lo non-T reg cells may depend on secretion of interleukin (IL)-12 and transforming growth factor (TGF)-β by tissues and their presence was correlated with tumor invasion by intestinal bacteria, especially Fusobacterium nucleatum. Thus, functionally distinct subpopulations of tumor-infiltrating FOXP3 + T cells contribute in opposing ways to determining CRC prognosis. Depletion of FOXP3 hi T reg cells from tumor tissues, which would augment antitumor immunity, could thus be used as an effective treatment strategy for CRCs and other cancers, whereas strategies that locally increase the population of FOXP3 lo non-T reg cells could be used to suppress or prevent tumor formation.
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