Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma.
OBJECTIVE
Regulatory T cells (Tregs) have been implicated as inhibitors of antitumoral immunity, and evidence suggests that elimination of Tregs may augment natural and pharmacologic immunity. We tested for the presence of putative Tregs within renal cell carcinoma (RCC) tumors.


METHODS
We identified 170 patients who underwent radical or partial nephrectomy for clear cell RCC between 2000 and 2002. Specimens were stained with anti-CD4, anti-CD25, and anti-Foxp3 antibodies and examined using confocal microscopy. Associations of CD4(+)CD25(+)Foxp3(-) and CD4(+)CD25(+)Foxp3(+) T cells with death from RCC were evaluated using Cox proportional hazards regression models.


RESULTS
At last follow-up, 46 of 170 patients had died; of these, 37 died from RCC at a median of 1.4 years following nephrectomy (range, 0-4.4). Among the 124 remaining patients, median follow-up was 3.7 years (range, 0-5.7). Forty-three (25.3%) tumors harbored CD4(+)CD25(+)Foxp3(+) T cells. The presence of Foxp3(+) T cells was not significantly associated with RCC death univariately. One hundred forty-three (84.1%) tumors harbored CD4(+)CD25(+)Foxp3(-) T cells. The indicator for >or=10% CD4(+)CD25(+)Foxp3(-) T cells was significantly associated with RCC death univariately [risk ratio (RR), 2.60; 95% confidence interval (95% CI), 1.35-4.98; P = 0.004], after adjusting for tumor B7-H1 expression (RR, 2.53; 95% CI, 1.32-4.85; P = 0.005) and lymphocytic infiltration (RR, 2.53; 95% CI, 1.32-4.87; P = 0.005).


CONCLUSIONS
Increased presence of CD4(+)CD25(+)Foxp3(+) T cells was not significantly associated with RCC death. In contrast, CD4(+)CD25(+)Foxp3(-) T cells, which may represent a unique set of Tregs or activated helper T cells, was significantly associated with outcome.
Siddiqui
Sameer A
SA
Department of Urology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Frigola
Xavier
X
Bonne-Annee
Sandra
S
Mercader
Maria
M
Kuntz
Susan M
SM
Krambeck
Amy E
AE
Sengupta
Shomik
S
Dong
Haidong
H
Cheville
John C
JC
Lohse
Christine M
CM
Krco
Christopher J
CJ
Webster
W Scott
WS
Leibovich
Bradley C
BC
Blute
Michael L
ML
Knutson
Keith L
KL
Kwon
Eugene D
ED
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007680:Kidney Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D018613:Microscopy, Confocal; D009367:Neoplasm Staging; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit