Increased intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in metastatic renal cell carcinoma.
OBJECTIVE
The administration of interleukin-2 (IL-2) may increase the frequency of peripherally circulating FOXP3-positive regulatory immune cells, thus potentially compromising this treatment option for patients with metastatic renal cell carcinoma. The impact of IL-2-based therapy on the accumulation of FOXP3-positive immune cells in the tumor microenvironment in metastatic renal cell carcinoma is unknown.


METHODS
Baseline (n = 58) and on-treatment (n = 42) tumor core biopsies were prospectively obtained from patients with clear cell metastatic renal cell carcinoma before and during IL-2-based immunotherapy. Immunohistochemical expression of FOXP3 was estimated by stereological counting technique and correlated with other immune cell subsets and overall survival.


RESULTS
A significant increase in absolute intratumoral FOXP3-positive immune cells was observed comparing baseline (median 23 cells/mm2; range, 0-183) and on-treatment biopsies (median, 89 cells/mm2; range, 11-388; P < 0.001). The relative increase in individual patients was median 4.7-fold, range 0.3 to 230. FOXP3-positive cells were positively correlated with CD3-positive, CD4-positive, and CD8-positive tumor-infiltrating immune cells at baseline and during treatment (P < 0.05 in all comparisons). All patients achieving high numbers (>180 cells/mm2) of on-treatment FOXP3-positive intratumoral immune cells were dead within 22 months (n = 11), whereas patients with low numbers (<180 cells/mm2) of on-treatment FOXP3-positive cells (n = 31) had a 5-year survival rate of 19% (hazard ratio, 2.2; confidence interval, 1.03-4.5; P = 0.043). All long-term survivors were characterized by low-baseline FOXP3-positive cells and a modest absolute rise in FOXP3-positive cells.


CONCLUSIONS
Intratumoral FOXP3-positive regulatory immune cells significantly increased during IL-2-based immunotherapy, and high numbers of on-treatment FOXP3-positive cells were correlated with poor prognosis in patients with metastatic renal cell carcinoma.
Jensen
Hanne Krogh
HK
Department of Oncology and Experimental Clinical Oncology, Aarhus University Hospital, Noerrebrogade 44, Aarhus C, Denmark. hajensen@rm.dk
Donskov
Frede
F
Nordsmark
Marianne
M
Marcussen
Niels
N
von der Maase
Hans
H
D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D055815:Young Adult
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2