CXCR3+ T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity.
Antitumor type I T-cell responses involving IFN-γ production are critical to control cancer, but the efficacy of this response is limited by a variety of immunosuppressive mechanisms that promote tumoral immune escape. One critical mechanism involves the accumulation of FOXP3(+) T regulatory cells (Treg), a class of suppressive T cells that prevent excessive tissue destruction caused by unchecked immune responses. Recent studies have revealed that FOXP3(+) Treg include distinct subsets specifically controlling over the corresponding effector subset. In particular, CXCR3(+) Treg have been described as a subset specialized in the control of type I T-cell responses in vivo. Here, we show that CXCR3(+) Treg are highly enriched in human ovarian carcinomas, particularly in solid tumor masses, where they represent the majority of Treg. Tumor-associated CXCR3(+.) Treg coexpress T-bet but do not secrete IFN-γ ex vivo and suppress proliferation and IFN-γ secretion of T effectors. In addition, they coexpress Helios, suggesting that they originate from natural Treg. Finally, we show that the proportion of CXCR3(+) Treg at tumor sites is directly correlated with that of CXCR3(+) T effectors, consistent with expression of CXCR3 ligands. Together, our findings support the concept that natural CXCR3(+) T-bet(+) Treg selectively accumulate in ovarian tumors to control type I T-cell responses, resulting in the collateral limitation of efficient antitumor immunity.
Institut National de la Santé et de la Recherche Médicale, Institut de Cancérologie de l'Ouest, Nantes-Saint Herblain, France.
Nassima
N
Redjimi
Caroline
C
Raffin
Isabelle
I
Raimbaud
Pascale
P
Pignon
Junko
J
Matsuzaki
Kunle
K
Odunsi
Danila
D
Valmori
Maha
M
Ayyoub
D002277:Carcinoma / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D000098815:T-bet Transcription Factor
C111431:IKZF2 protein, human; D008024:Ligands; D054367:Receptors, CXCR3; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D051740:Ikaros Transcription Factor; D007371:Interferon-gamma