Abstract 5522: Elucidating the role of P-selectin/P-selectin ligand-1 axis in lung cancer brain metastasis
Authors: Salomon Koren , Yeini Eilam , Frommer Neta , Kamer Irisi , Bar Jair , Barshack Iris , Satchi-Fainaro Ronit 
Published: March 2024

Abstract
Lung cancer (LC) stands as a prominent cause of cancer-related mortality. Brain metastasis (BM) is a common occurrence in LC, constituting nearly 50% of all BM cases with the brain emerging as the preferred site for LC metastasis. Unfortunately, current LCBM treatment options yield limited success, as reflected in the median survival of BM patients at 7.8 months. Consequently, there is an imperative need for novel and more efficacious therapeutic approaches targeting LCBM. Evidence suggests that brain microenvironment cells, particularly microglia and tumor-associated macrophages (TAMs), play a pivotal role in facilitating the colonization and growth of LCBM. Previous investigations from our lab have identified the involvement of the P-selectin/P-selectin glycoprotein ligand-1 (SELP/PSGL-1) axis in microglia/TAMs immunophenotypes, promoting pro-tumorigenic activity. This led us to explore the role of the SELP/PSGL-1 axis in the interactions between LCBM cells and the brain microenvironment1. Thus, we conducted Immunostaining on human tissue samples, revealing increased expression of SELP, PSGL-1, PD-1, PD-L1, IBA-1, and CD68 in LCBM tissues. Simultaneously, we employed advanced 3D models to investigate the intricate interactions between cancer cells and microglia/TAMs. Actively inhibiting the SELP/PSGL-1 axis with pharmacological agents led to a significant decrease in migration and invasion when LC cells were co-cultured with microglia and TAMs. Moreover, SELP inhibition prompted a shift in microglia/TAMs state towards an M1-like phenotype, enhancing the ability of CD4/CD8 cells to target cancer cells in our unique 3D LCBM models. This effect was further enhanced when co-treated with a PD-1 inhibitor, demonstrating a potential synergistic impact in targeting both pathways for therapeutic intervention. Our results suggest that combining SELP inhibition with other immunomodulators, including a small molecule PD-L1 inhibitor developed in our lab2, could synergistically enhance both innate and adaptive anti-tumor immune responses. Taken together, this study may enhance our understanding of LCBM immunogenicity and contribute to the development of novel immunotherapeutic approaches that can improve patient outcomes.1.Yeini, E., et al. P-selectin axis plays a key role in microglia immunophenotype and glioblastoma progression. Nat Commun 12, 1912 (2021). 2. Acúrcio, R.C., et al. Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment. J Immunother Cancer 10(2022).
Citation Format: Koren Salomon, Eilam Yeini, Neta Frommer, Irisi Kamer, Jair Bar, Iris Barshack, Ronit Satchi-Fainaro. Elucidating the role of P-selectin/P-selectin ligand-1 axis in lung cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5522.