Two FOXP3+CD4+ T cell subpopulations distinctly control the prognosis of colorectal cancers

Abstract

CD4(+) T cells that express the forkhead box P3 (FOXP3) transcription factor function as regulatory T (Treg) cells and hinder effective immune responses against cancer cells. Abundant Treg cell infiltration into tumors is associated with poor clinical outcomes in various types of cancers. However, the role of Treg 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) Treg 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(+) Treg 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) Treg cell infiltration. Development of such inflammatory FOXP3(lo) non-Treg 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) Treg 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-Treg cells could be used to suppress or prevent tumor formation.

Flicr , a long noncoding RNA, modulates Foxp3 expression and autoimmunity

“…FoxP3 does not merely obey on/off regulation to dictate Treg repressive functions, but can be tuned in response to different environmental cues, particularly in conditions of limiting IL-2 (2,4,18,19). These results show that IL-2 has two means of enhancing Foxp3 expression, directly via activation of the Cns2 enhancer and indirectly by repressing Flicr, the attenuator of Foxp3.…”

“…In their absence, humans and mice develop devastating autoimmune and lymphoproliferative pathologies (3). Although beneficial in preventing runaway immune activation, supporting tolerance of symbiotic microbes, and restraining tissue destruction in autoimmune lesions, their regulatory activity can also be deleterious, for example, by inhibiting antitumor (4) or antiviral responses (2,5).…”

Infiltration of effector regulatory T cells predicts poor prognosis of diffuse large B-cell lymphoma, not otherwise specified

“…8,12 In addition, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a negative immunomodulator expressed by activated T cells is also expressed by eTregs and is essential for their suppressive function. 8,13,14 Despite the immunosuppressive function of Tregs on antitumor immune responses, a high infiltration of Tregs, as defined by FOXP3 expression, is reportedly associated with a better prognosis of patients with DLBCL, NOS. 15 To reconcile this discrepancy, the present study aimed at retrospectively evaluating the relationship between the infiltration of eTregs (FOXP3/CTLA-4 double-positive cells) and the prognosis of patients with DLBCL, NOS.…”

Inter-patient and Intra-tumor Heterogeneity in the Sensitivity to Tumor-targeted Immunity in Colorectal Cancer

“…Inter-patient heterogeneity in tumor immunity result from genetic background involved in carcinogenesis, such as mismatch repair gene deficiency and POLE mutation, and personal disease-modifying factors, such as composition of intestinal bacterial flora 15,16) , smoking status and pre-existing disease. These factors of inter-patient heterogeneity were previously evaluated by analyzing therapeutic response data, clustering analysis preceded by DNA microarray analysis, and whole exome sequencing which revealed DNA mutation load found in each patient ( Table 1) .…”