Abstract 2557: Slit2 inhibits small cell lung cancer by targeting tumor microenvironment

Abstract

Abstract Small cell lung cancer (SCLC) is the deadliest subtype of lung cancer with a 5-year survival rate of <5% in extensive-state disease and is designated by US Congress as a “recalcitrant cancer”. Recently approved by FDA, immune checkpoint blockade (ICB) immunotherapy showed marginally improved survival and only in a few patients, suggesting an inert immune tumor microenvironment (TME) and the existence of SCLC subtypes. Therefore, there is a significant need to develop more effective therapies for SCLC. In addition to the nearly universal biallelic inactivation of Rb and Tp53 genes in human SCLC tumors, comprehensive genome-wide screening studies have identified major co-occurring mutations in PTEN, CREBBP, EP300, SLIT2, MLL, COBL, and EPHA7 genes. Among them, SLIT2 showed the highest level of genomic abnormalities defined by a pronounced clustering of mutations and frequent genomic loss. However, the role of Slit2 in SCLC has not been defined yet. By using genetically engineered human SCLC cells overexpressing Slit2 or recombinant Slit2 (rSlit2) protein, we show that Slit2 inhibits SCLC cells proliferation, migration, and invasion properties and tumor sphere formation ability of drug-resistant SCLC cells in vitro. The mechanistic studies have identified inhibition of AKT and β-catenin mediated signaling pathways by Slit2 overexpression. Next, we implanted human SCLC cell lines into the immunocompromised NSG mice subcutaneously followed by treatment with rSlit2 or sterile saline. Analysis of tumor volume over the 4 weeks showed that rSlit2 treatment significantly reduced the growth of SCLC tumors. Further analysis of tumors showed that rSlit2 treated tumors harbor less M2-like CD206+ macrophages. Overall, these results suggest that Slit2 possesses tumor suppressive properties and could be developed as a novel therapeutic agent against SCLC. Citation Format: Dinesh K. Ahirwar, Manish Charan, Swati Misri, Konstantin Shilo, Ramesh Ganju. Slit2 inhibits small cell lung cancer by targeting tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2557.