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

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Abstract
In recent studies, a crucial role for IFN-γ in immunosurveillance of tumours and in IL-12 immunotherapy has been suggested. Nevertheless, little is known about the relevance of IFN-γ 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-γ 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-γ 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-γ 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.