Adriamycin-mediated potentiation of cytotoxicity against freshly isolated bladder cancer cells by autologous non-activated peripheral blood lymphocytes and tumor infiltrating lymphocytes

Purpose: Previous studies indicated that cancer patients lack functional an ti-tumor cytotoxic lymphocytes. However, anti-tumor cytotoxic lymphocytes m ay coexist with immunoresistant tumor cells. We reasoned that anti-tumor cy totoxic activity of lymphocytes may be revealed if the tumor cells are sens itized to killing. It has been reported that adriamycin (ADR) exhibits vari ous immunomodulating activities. In the present study, we investigate the e ffect of ADR on the susceptibility of freshly isolated bladder cancer cells to lysis by autologous nonactivated peripheral blood lymphocytes (PBL) and tumor infiltrating lymphocytes (TIL). Materials and Methods: Cytotoxicity was determined by a 1-day microculture tetrazolium dye assay. Results: Treatment of ADR-resistant fresh bladder cancer cells with ADR at 0.1 mu g./ml. or more for 3 hours or more enhanced their susceptibility to lysis by autologous PBL. This ADR-induced enhancement of susceptibility of fresh bladder cancer cells to lysis by PBL was also observed when lymphokin e activated killer cells, purified natural killer cells and T lymphocytes w ere used as effector cells. Furthermore, while cytotoxicity of freshly deri ved TIL against autologous bladder cancer cells was minimal, significant cy totoxicity was observed with ADR-treated bladder cancer cells. The ADR anal ogs, epirubicin and pirarubicin, also enhanced the susceptibility of bladde r cancer cells to lysis by autologous PBL. Treatment of bladder cancer cell s with ADR had no effect on the expression of MHC class I on the cancer cel ls or the frequency of bladder cancer target cell conjugates to autologous PBL. Treatment of bladder cancer cells with ADR augmented their sensitivity to anti-Fas monoclonal antibody and tumor necrosis factor-or. Pretreatment of effector cells with ADR had no effect on their cytotoxic function. Conclusions: These findings demonstrate that PBL and TIL in patients with b ladder cancer exhibit anti-tumor cytotoxic function, but their function is not manifested due to development or acquisition of tumor cell resistance t o killing. However, the resistance of bladder cancer cells to killing by cy totoxic lymphocytes is overcome if cancer cells are sensitized by subtoxic concentrations of ADR. These findings suggest that treatment of bladder can cer patients with low doses of ADR may sensitize the cancer cells to killin g by autologous circulating and tumor infiltrating lymphocytes and may be a novel immunotherapeutic modality for the treatment of drug-resistant and/o r immune-resistant bladder cancer.