IL-2 therapy increases intratumoral FOXP3

+ regulatory immune cells in patients with metastatic renal cell carcinoma

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Abstract:

Background.

Interleukin-2 (IL-2) based therapy is currently the only curative treatment for patients with metastatic renal cell carcinoma (mRCC). However, administration of IL-2 increases the frequency of circulating FOXP3+ regulatory immune cells, potentially compromising an effective anti-tumor immune response. The present study investigated the impact of IL-2 based therapy on FOXP3+ regulatory immune cells in repeated tumor tissue biopsies from patients with mRCC. Methods.

Baseline and on-treatment tumor core biopsies were prospectively obtained from 48 patients treated with IL-2 based immunotherapy. Follow-up was at least five years. Immunohistochemical expression of FOXP3 was evaluated using Clone CM299b, Biocare Medical. The number of cells/mm2 was estimated using stereological counting technique and correlated with other immune cell subtypes (continuous values) and overall survival (dichotomized by the upper quartile). Results.

A significant increase in intratumoral FOXP3+ immune cells was observed when comparing baseline (median 15/mm2, range 0–123) and on-treatment biopsies (median 70/mm2, range 7–388), p<0.001. The relative increase in individual patients was median 5 fold, range 0.1 – 230, p<0.001. No association between the absolute numbers of FOXP3+ and objective response was observed. FOXP3+ cells were positively correlated to CD3+, CD4+, CD8+ and CD57+ tumor-infiltrating immune cells at baseline, and to CD4+, CD8+ and CD66b+ during treatment (p in all comparisons<0.05). All patients achieving high numbers of on-treatment FOXP3+ intratumoral regulatory immune cells (>175/mm2) (N=12) were dead within 21 months, whereas patients with low numbers of on-treatment FOXP3+ cells (N=36) had a 5 year survival rate of 22%, (HR 2.2, CI 1.1–4.5, p=0.02). Conclusions.

This is the first report of intratumoral FOXP3+ regulatory immune cells in mRCC patients treated with Interleukin-2. Intratumoral FOXP3+ regulatory immune cells were significantly increased by IL-2 based immunotherapy. High numbers of on-treatment FOXP3+ were correlated with poor prognosis in patients with mRCC.

Document Type: Abstract

DOI: http://dx.doi.org/10.1111/j.1600-0463.2008.001165_17.x

Affiliations: 1: Onkologisk Afdeling, Århus Universitetshospital, Nørrebrogade 44, 8000 Århus C 2: Afd. For Klinisk Patologi, Odense Universitetshospital, Winsløwparken 15, 5000 Odense C 3: Onkologisk Klinik, Rigshospitalet, Blegdamsvej 9, 2100 København Ø

Publication date: May 1, 2008

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