Elevated FOXP3, in the absence of FOXP3lo T cells, is associated with poor colon cancer prognosis.
Major finding: Elevated FOXP3, in the absence of FOXP3lo T cells, is associated with poor colon cancer prognosis.
Clinical relevance: IL12A and TGFB1 may be prognostic for and distinguish between FOXP3hi and FOXP3lo colorectal cancer.
Impact: Depletion of FOXP3hi Tregs and induction of FOXP3lo T cells may be a potential therapy for colorectal cancer.
Regulatory T cells (Treg) are a subpopulation of CD4+ T cells that express the transcription factor forkhead box P3 (FOXP3) and suppress the induction and proliferation of effector T cells to impair antitumor immunity. However, elevated Treg infiltration of colorectal tumors has been correlated with both increased and poorer patient survival, due to the functional and phenotypic heterogeneity of FOXP3+CD4+ T cells. It has been shown that expression of CD45RA and level of FOXP3 expression define two distinct subpopulations of FOXP3+CD4+ T cells which are immunosuppressive (CD45A−FOXP3hi) or proinflammatory (CD45A−FOXP3lo). To ascertain the contribution of FOXP3+CD4+ T-cell subpopulations to the prognosis of patients with colorectal cancer, Saito and colleagues stratified colorectal tumors based upon the frequency of each of the two FOXP3+CD4+ T-cell subpopulations. CD45A−FOXP3lo T cells were present at low frequency in type A tumors and at high frequency in type B tumors, whereas CD45A−FOXP3hi T cells were present at similar frequencies in both types A and B tumors. Type B tumors, unlike type A tumors, exhibited upregulation of genes related to immune response and inflammation, particularly IL12A and TGFB1, which were the most differentially expressed cytokines in type B versus type A tumors. Consistent with these findings, treatment with IL12A and TGFβ induced FOXP3lo T cells but not FOXP3hi Tregs. High FOXP3 expression was associated with poor patient prognosis in IL12AloTGFB1lo type A tumors and with better patient prognosis in IL12AhiTGFB1hi type B tumors. The presence of FOXP3lo T cells was correlated with the presence of the intestinal bacterium Fusobaterium nucleatum, which was present at higher frequencies in IL12AhiTGFB1hi type B tumors than in IL12AloTGFB1lo type A tumors. Together, these results show that functionally distinct FOXP3+ T-cell subpopulations are associated with different colorectal cancer prognoses, and that modulation of these FOXP3+ T-cell subsets may be a potential therapeutic strategy for patients with colorectal cancer.