IFN-gamma and IL-12 but not IL-10 are required for local tumour surveillance in a syngeneic model of orthotopic bladder cancer

In recent studies, a crucial role for IFN-gamma in immunosurveillance of tumours and in IL-12 immunotherapy has been suggested. Nevertheless, little is known about the relevance of IFN-gamma and IL-12 for tumour surveillance in noncytokine immunotherapy. Adjuvant immunotherapy with viable BCG (Bacillus Calmette--Guérin) is considered to be the most powerful clinical treatment regimen of bladder cancer and is known to induce a variety of proinflammatory cytokines. Consequently, we analysed the antitumour response of IFN-gamma knockout (KO), IL-12 KO and IL-10 KO mice in the absence and presence of BCG immunotherapy in a syngeneic orthotopic model of bladder cancer. IFN-gamma KO and IL-12 KO mice died much earlier and by far smaller tumour inocula compared to wildtype mice, while this intrinsic antitumour response was not altered in IL-10 KO mice. BCG immunotherapy was effective in wildtype mice, but totally ineffective in IFN-gamma KO and IL-12 KO mice. BCG induced a massive local immune response in the bladder of treated animals. This response was markedly increased in IL-10 KO mice, which coincides with increased therapeutic efficacy in this mouse strain compared with wildtype mice. Our data establish a crucial role for a Th1 type immune response in the intrinsic and immunotherapeutic control of local orthotopic bladder cancer.