Development of chemoimmunothempy against renal cancer by up-regulation of co-stimulatory molecules

点击翻译按钮获取中文摘要

In this study, we investigated the effect of adriamycin on the susceptibility of human renal cell carcinoma (RCC) cells to lysis by peripheral blood lymphocytes (PBL) and tumor infiltrating lymphocytes (TIL). We also explored molecular mechanisms involved in adriamycin modulating susceptibility of RCC cells to PBL and TIL. We found that pretreatment of RCC cells with subtoxic concentrations of adriamycin resulted in a potentiation of anticancer activities of PBL and TIL. Adriamycin up-regulated leukocyte function-associated antigen-3 (LFA-3) and intercellular adhesion molecule-1 (ICAM-1) expressions in RCC cells. LFA-3 and ICAM-1 are critical in the binding and killing of cytotoxic T lymphocytes against cancer cells. Up-regulation of LFA-3 and ICAM-1 was also observed in RCC cells treated with two derivatives of adriamycin, epirubicin and pirarubicin. Adriamycin further significantly increased the bindings of PBL to RCC cells. In addition, adriamycin sensitized RCC cells to Fas- and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity. These findings suggest that treatment of RCC patients with low doses of adriamycin may sensitize the RCC cells to killing by PBL and TIL, and may be a novel immunotherapeutic modality for the treatment of drug-resistant and/or immune-resistant RCC. The induction of LFA-3 and ICAM-1 by adriamycin may involve in the enhancement of susceptibility of PBL and TIL-mediated cytolysis in human RCC cells. In the experiments of developing molecular targeted therapy using Lexatumumab, an agonistic TRAIL-receptor 2 (TRAIL-R2) antibody, we demonstrated synergistic cytotoxic effect of adriamycin and Lexatumumab against RCC cells. We further demonstrated that the synergistic cytotoxicity of Lexatumumab and adriamycin was realized by inducing apoptosis through the induction of TRAIL-R2 and the intrinsic caspase pathway.