Title

Direct Tumor Killing and Immunotherapy through Anti-SerpinB9 Therapy.

Document Type

Article

Publication Date

11-25-2020

Keywords

JMG, JAXCC

JAX Source

Cell 2020 Nov 25; 183(5):1219-1233.e18

Volume

183

Issue

5

First Page

1219

Last Page

1233

ISSN

1097-4172

PMID

33242418

DOI

https://doi.org/10.1016/j.cell.2020.10.045

Grant

AI132963; OD018259; CA034196

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.

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