Abstract B089: Assessing integrin αvβ5 as a therapeutic target suppressing tumor progression and enhancing immune responses in non-small cell lung cancer

Abstract Lung cancer is the leading cause of cancer related deaths worldwide, with non-small cell lung cancer (NSCLC) being the most common subtype. Current treatments, including targeted therapy and immunotherapy, only yield durable clinical responses for a subset of patients highlighting the need for new treatment options. Integrins (ITGs) are a diverse class of heterodimeric, transmembrane receptors that bind to the extracellular matrix (ECM) and the cytoskeleton to integrate bi-directional signals between the extracellular environment and cell interior. Each integrin consists of one of 18 α subunits paired with one of 6 β subunits to create the 24 known αβ ITGs in mammals. Notably, the β5 subunit only forms a heterodimer with αv. ITGs are expressed at low levels in normal tissue and can be upregulated in cancer cells in response to stress signals in the tumor microenvironment (TME). Altered expression of ITGs is associated with increased cell proliferation, metastasis, and immune evasion. Through data mining of a genome wide CRISPR screening publicly available at the DepMap portal, we identified ITG αvβ5 as a novel cancer dependency in approximately 40% of NSCLC cell lines. Using small molecule ITG αv inhibitors, we have mirrored sensitivity of NSCLC cell lines to their ITG αvβ5 CRISPR scores, suggesting that these inhibitors function specifically through ITG αvβ5. RNA sequencing analysis following αvβ5 inhibition in human NSCLC cell lines revealed downregulation of Yes-associated protein (YAP) and E2F1 target genes with alterations in gene ontologies associated with cell cycling and cell death in sensitive, but not resistant, lines. Additionally, CRISPR knock out (KO) of ITG β5 eliminating surface expression of ITG αvβ5 resulted in decreased cell cycle progression in sensitive NSCLC lines. Transduced NSCLC cells lines with inducible expression of constitutively active YAP with a serine to alanine mutation (S127A) that remains active revealed partial rescue of cells sensitive to αvβ5 inhibition in vitro. This highlights the potential role for YAP in mediating the effect of ITG αvβ5 inhibition. YAP is also implicated in establishment of an immunosuppressive TME through its activation of PD-L1 transcription, correlation with PD-L1 expression in lung adenocarcinoma, and facilitation of cytokine release that recruit immune suppressive cell populations. We observed further immune related changes, specifically perturbations to interferon (IFN) pathways, in response to ITG αvβ5 inhibition. In NSCLC murine models, pharmacological inhibition of ITG αvβ5 reduced tumor growth and increased immune activation. These findings support ITG αvβ5 and its regulation of YAP activity as a unique non-mutant therapeutic target of cancer dependency with potential to modulate host immune responses in NSCLC. Citation Format: Bitta P Kahangi, William P Crosson, Ji-Ann Lee, Nalani Coleman, Camelia Dumitras, Hong Jiang, Tianhao Zhang, Jensen Abascal, Edgar Perez Reyes, Austin Rennels, Ramin Salehi-Rad, Linh M Tran, Michael Palazzolo, Dylan Conklin, Steven M Dubinett, Bin Liu. Assessing integrin αvβ5 as a therapeutic target suppressing tumor progression and enhancing immune responses in non-small cell lung cancer [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B089.