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Presentation of Renal Tumor Antigens by Human Dendritic Cells Activates Tumor-infiltrating Lymphocytes against Autologous Tumor: Implications for Live Kidney Cancer Vaccines¹

University of California at Los Angeles, Kidney Cancer Program, Immunotherapy Laboratory, Department of Urology [P. M., C-L. T., R. K., A. H., S. F., J. d., A. B.]; and Divisions of Hematology-Oncology [B. G., R. F.] and Pulmonary Medicine [S. K., M. D. R.], Department of Medicine and Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, California 90095-1738

ABSTRACT

The clinical impact of dendritic cells (DCs) in the treatment of human cancer depends on their unique role as the most potent antigen-presenting cells that are capable of priming an antitumor T-cell response. Here, we demonstrate that functional DCs can be generated from peripheral blood of patients with metastatic renal cell carcinoma (RCC) by culture of monocytes/macrophages (CD14⁺) in autologous serum containing medium (RPMI) in the presence of granulocyte macrophage colony-stimulating factor and interleukin (IL) 4. For testing the capability of RCC-antigen uptake and processing, we loaded these DCs with autologous tumor lysate (TuLy) using liposomes, after which cytometric analysis of the DCs revealed a markedly increased expression of HLA class I antigen and a persistent high expression of class II. The immunogenicity of DC-TuLy was further tested in cultures of renal tumor infiltrating lymphocytes (TILs) cultured in low-dose IL-2 (20 Biologic Response Modifier Program units/ml). A synergistic effect of DC-TuLy and IL-2 in stimulating a T cell-dependent immune response was demonstrated by: (a) the increase of growth expansion of TILs (9.4–14.3-fold; day 21); (b) the up-regulation of the CD3⁺CD56^-TcR⁺ (both CD4⁺ and CD8⁺) cell population; (c) the augmentation of T cell-restricted autologous tumor lysis; and (d) the enhancement of IFN-, tumor necrosis factor-, granulocyte macrophage colony-stimulating factor, and IL-6 mRNA expression by TILs. Taken together, these data implicate that DC-TuLy can activate immunosuppressed TIL via an induction of enhanced antitumor CTL responses associated with production of Th1 cells. This indicates a potential role of DC-TuLy vaccines for induction of active immunity in patients with advanced RCC.

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