Abstract 3685: Targeting a novel cell surface serine protease TMPRSS11B for lung cancer therapy

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. Patients have few therapeutic options, and disease progression is inevitable. Anti-PD-1/PD-L1 antibodies can induce potent anti-tumor immunity and have been approved as a first-line therapy for non-small cell lung cancer (NSCLC). However, only ~20% of all NSCLCs benefit from checkpoint blockade, underscoring the critical need for the development of new and innovative approaches to identify actionable therapeutic targets to treat NSCLC. We identified the Transmembrane Serine Protease TMPRSS11B as a novel gene that promotes the transformation of human bronchial epithelial cells in vitro and induces tumorigenesis in vivo (Updegraff et al., Cell Reports, 2018). Our data show that TMPRSS11B promotes solubilization of Basigin, an obligate chaperone of the lactate monocarboxylate transporters MCT1 and MCT4, and that TMPRSS11B interacts and co-localizes with Basigin and MCT4. Moreover, Basigin release mediated by TMPRSS11B enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis. This is of significant interest because TMPRSS11B is frequently overexpressed in human lung squamous cell cancers (LSCC) and high expression is associated with poor survival of NSCLC patients. Moreover, as a cell surface protein and enzyme, TMPRSS11B represents an exciting putative target for therapeutic intervention. Our new studies demonstrate that the catalytic activity of TMPRSS11B may be important for the interaction with Basigin and enhanced lactate export. We also evaluated the effect of Tmprss11b depletion in the KLN205 syngeneic LSCC mouse model. CRISPR/Cas9 knockout of Tmprss11b in KLN205 LSCC cells significantly reduced tumor burden in immunocompetent DBA/2 WT mice. Moreover, mass spectrometry analysis revealed TMPRSS11B-interacting proteins that may represent novel substrates of this enzyme. Current studies are focused on elucidating the molecular mechanisms through which TMPRSS11B promotes tumorigenesis and investigating the efficacy of TMPRSS11B inhibition in syngeneic and autochthonous mouse models of LSCC, where the effects on immune cell function will be assessed. Citation Format: Hari Shankar Sunil, Barrett Updegraff, Jingfei Zhu, Bret M. Evers, John D. Minna, Ralph J. Deberardinis, Trudy G. Oliver, Kathryn A. O'Donnell. Targeting a novel cell surface serine protease TMPRSS11B for lung cancer therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3685.