Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers.
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.
Experimental Immunology, World Premier International Research Center (WPI), Immunology Frontier Research Center, Graduate School of Medicine, Osaka University, Osaka, Japan.|Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
Takuro
T
Saito
Experimental Immunology, World Premier International Research Center (WPI), Immunology Frontier Research Center, Graduate School of Medicine, Osaka University, Osaka, Japan.
Hiroyoshi
H
Nishikawa
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.|Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Hisashi
0000-0002-5444-6193
H
Wada
RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan.
Yuji
Y
Nagano
Experimental Immunology, World Premier International Research Center (WPI), Immunology Frontier Research Center, Graduate School of Medicine, Osaka University, Osaka, Japan.
Daisuke
D
Sugiyama
RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan.
Koji
K
Atarashi
Experimental Immunology, World Premier International Research Center (WPI), Immunology Frontier Research Center, Graduate School of Medicine, Osaka University, Osaka, Japan.
Yuka
Y
Maeda
Experimental Immunology, World Premier International Research Center (WPI), Immunology Frontier Research Center, Graduate School of Medicine, Osaka University, Osaka, Japan.
Masahide
0000-0002-8651-4445
M
Hamaguchi
Experimental Immunology, World Premier International Research Center (WPI), Immunology Frontier Research Center, Graduate School of Medicine, Osaka University, Osaka, Japan.
Naganari
N
Ohkura
Department of Pathology, Institute of Medical Science (Medical Research Center), Tokyo Medical University, Tokyo, Japan.
Eiichi
E
Sato
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
Hirotsugu
H
Nagase
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
Junichi
J
Nishimura
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
Hirofumi
H
Yamamoto
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
Shuji
S
Takiguchi
RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan.
Takeshi
T
Tanoue
Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan.
Wataru
W
Suda
School of Veterinary Medicine, Azabu University, Kanagawa, Japan.
Hidetoshi
H
Morita
Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan.
Masahira
M
Hattori
RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan.
Kenya
K
Honda
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
Masaki
M
Mori
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
Yuichiro
Y
Doki
Experimental Immunology, World Premier International Research Center (WPI), Immunology Frontier Research Center, Graduate School of Medicine, Osaka University, Osaka, Japan.
Shimon
S
Sakaguchi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D013505:Digestive System Surgical Procedures; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D053765:Interleukin-12 Subunit p35 / Q000276:immunology / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508858:IL12A protein, human; D053765:Interleukin-12 Subunit p35; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1