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Published on: January 17, 2025
Direct Tumor Killing and Immunotherapy through Anti-SerpinB9 Therapy
Liwei Jiang1, Yi-Jun Wang1, Jing Zhao1
1Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
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.
Insights
Inhibiting serine protease inhibitor SerpinB9 (Sb9) directly kills cancer cells and enhances anti-tumor immunity. Combining Sb9 deficiency in both tumor and host maximizes cancer growth control and survival in mice.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Cancer therapies aim to eliminate tumors directly or via immune responses, with combined approaches showing variable success.
- Serine protease inhibitor SerpinB9 (Sb9) plays a role in tumor cell survival and immune modulation within the tumor microenvironment (TME).
Purpose of the Study:
- To investigate the therapeutic potential of genetic ablation of SerpinB9 (Sb9) for controlling cancer growth.
- To explore the combined effects of Sb9 deficiency on direct tumor killing and host anti-tumor immunity.
Main Methods:
- Genetic ablation of SerpinB9 (Sb9) in mouse models of cancer.
- Assessment of tumor cell death, T cell-mediated immunity, and immunosuppressive cell populations within the TME.
- Evaluation of tumor growth, survival rates, and therapeutic efficacy of Sb9 inhibition.
Main Results:
- Sb9 deficiency led to granzyme B (GrB)-dependent tumor cell death.
- Sb9-deficient mice displayed enhanced T cell-based anti-tumor immunity.
- A decline in GrB-expressing immunosuppressive cells was observed in the TME of Sb9-deficient mice.
- Maximal tumor growth control and increased survival were achieved when both tumor and host were Sb9-deficient.
Conclusions:
- Targeting SerpinB9 (Sb9) offers a novel therapeutic strategy for cancer by combining direct tumor killing with the potentiation of anti-tumor immunity.
- Sb9 inhibition represents a promising modality for interfering with the TME and enhancing immunotherapy efficacy.
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