Infiltration of Activated Dendritic Cells and T Cells in Renal Cell Carcinoma Following Combined Cytokine Immunotherapy

Abstract

Objectives: In a phase I study the feasibility, toxicity and immunological effects of peri-operative cytokine immunotherapy of renal cell carcinoma were studied. Main goals were to determine the maximal tolerable dose and detailed in situ analysis of tumor infiltrates. Methods: Fifteen patients with renal cell carcinoma, undergoing nephrectomy, received subcutaneous immunotherapy, consisting of low-dose IL-2, IFNα and GM-CSF, from day −3 prior, until day +5 following surgery in a dose escalation study. Infiltrates from resected tumor tissues from patients undergoing immunotherapy or control patients that underwent nephrectomy only, were examined using quantitative immunohistological analysis and 3-color immunofluorescence staining and confocal laser scanning microscope analysis. Results: Toxicity was limited and the maximal tolerable dose was established. In peripheral blood an increase was found in total lymphocytes, (activated) T cells, NK cells and monocytes. Quantitative immunohistological analysis of tumor infiltrates showed enhanced numbers of CD3+ T cells, S100+ DC, CD83+ DC and IL-2 receptor positive cells (4-fold, 2-fold, 10-fold and 20-fold, respectively, compared to controls). In treated patients preferential invasion was observed of TNFα positive CD8+ T cells and DC, positive for DC-SIGN (CD209), CD83, CD80, IL-12 and the DC specific chemokine, DC-CK1 (CCL18). Conclusions: These findings show increased infiltration of activated, mature DC and functionally active CD8+ T cells in renal tumors, which may suggest clinical potential of cytokine immunotherapy.