Identification of CD8+CD25+Foxp3+ suppressive T cells in colorectal cancer tissue.
BACKGROUND
The antitumoral immune response is one determinant of colorectal cancer (CRC) outcome. Recent work suggests that Foxp3(+)CD25(+)CD4(+) regulatory T cells (T4reg) might hamper effective immunosurveillance of emerging cancer cells and impede effective immune responses to established tumours. In this descriptive study, we analysed blood and tissue regulatory T cell populations in patients with CRC.


METHODS
Blood and tissue regulatory Foxp3(+) T cells from 40 patients with CRC were compared to regulatory Foxp3(+) T cells from normal colonic tissue and from blood of 26 healthy volunteers. Flow cytometry was used to quantify and phenotype all Foxp3(+) T cell populations. Correlations were sought with the tumour stage and with micro-invasive status. The suppressive capacity of regulatory Foxp3(+) T cells was assessed by their effect on CD4(+)CD25(-) T cell proliferation in vitro and by their capacity to inhibit cytokine production by conventional T cells.


RESULTS
We found a significant increase of CD8(+)CD25(+)Foxp3(+) cells (T8reg) in blood and CRC tissue; their phenotype was close to that of T4reg. T8reg cells infiltrating CRC were activated, as suggested by increased cytoxic T lymphocyte-associated antigen-4, glucocorticoid-induced tumour necrosis factor-related protein, and transforming growth factor (TGF)beta1 expression compared to T8reg from normal autologous colonic tissue. Moreover, T8reg were able to suppress CD4(+)CD25(-) T cell proliferation and Th1 cytokine production ex vivo, demonstrating that tumour-infiltrating T8reg have strong suppressive capacities. T8reg numbers correlated with the tumour stage and with micro-invasive status. Finally, interleukin 6 and TGF beta 1 synergistically induced the generation of CD8(+)CD25(+)Foxp3(+) T cells ex vivo.


CONCLUSIONS
We have identified a new regulatory T cell population (CD8(+)Foxp3(+)) in colorectal tumours. After isolation from cancer tissue these CD8(+)Foxp3(+) cells demonstrated strong immunosuppressive properties in vitro. These data suggest that these cells may contribute to tumoral immune escape and disease progression.
Chaput
N
N
Département de Biothérapie, Groupe Hospitalier Pitié Salpêtrière, Paris, France.
Louafi
S
S
Bardier
A
A
Charlotte
F
F
Vaillant
J-C
JC
Ménégaux
F
F
Rosenzwajg
M
M
Lemoine
F
F
Klatzmann
D
D
Taieb
J
J
D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis; D009367:Neoplasm Staging; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D009363:Neoplasm Proteins