Direct Tumor Killing and Immunotherapy through Anti-SerpinB9 Therapy

Cancer therapies kill tumors either directly or indirectly by evoking immune responses and have been combined with varying levels of success. Here, we describe a paradigm to control cancer growth that is based on both direct tumor killing and the triggering of protective immunity. Genetic ablation of serine protease inhibitor SerpinB9 (Sb9) results in the death of tumor cells in a granzyme B (GrB)-dependent manner. Sb9-deficient mice exhibited protective T cell-based host immunity to tumors in association with a decline in GrB-expressing immunosuppressive cells within the tumor microenvironment (TME). Maximal protection against tumor development was observed when the tumor and host were deficient in Sb9. The therapeutic utility of Sb9 inhibition was demonstrated by the control of tumor growth, resulting in increased survival times in mice. Our studies describe a molecular target that permits a combination of tumor ablation, interference within the TME, and immunotherapy in one potential modality. [Display omitted] •SerpinB9 protects cancer cells from their own granzyme B•SerpinB9 expression in CAFs, MDSCs, and TAMs can promote tumor growth•Deletion of serpinB9 in both the tumor and host suppresses tumor growth markedly•SerpinB9 inhibition can target cancer cells, CAFs, MDSCs, and TAMs simultaneously SerpinB9 is important for tumor cell survival and for the presence of immunosuppressive cells in the tumor microenvironment, and a small-molecule inhibitor of SerpinB9 can reduce tumor growth and increase tumor immunogenicity in several mouse models of cancer.