Abstract 5140: ITGB6 as a predictive biomarker for overall prognosis and PD-(L)1 immune checkpoint blockade response in various cancer types

Abstract

Abstract Our previous work studying the effects of integrin αvβ6 knockdown in cancer cells demonstrated αvβ6 as a method of T cell suppression in a co-culture model. ITGB6, the gene encoding the β6 subunit of αvβ6, is a potent prognostic marker across multiple cancer types. As a major activator of latent TGFβ, αvβ6, and consequently, ITGB6, has considerable therapeutic implications due to the immunosuppressive effect that activated TGFβ has on the tumor microenvironment. A Human Protein Atlas search of ITGB6 expression surveyed the upregulation of ITGB6 across cancer types. Cancer ITGB6 expression was then compared to expression in paired adjacent normal tissue using the TNMplot tool (Bartha, 2021) on a concatenated set of GEO, GTex, TCGA, and TARGET RNA-seq databases. Kaplan-Meier curves were generated using TCGA mRNA data through the cBio portal, splitting the cohorts according to an ITGB6 mRNA expression threshold of one standard deviation above the mean (z-score ± 1.0). ITGB6 expression and immune checkpoint blockade (ICB) response were evaluated with the Kaplan-Meier Plotter tool (Kovacs, 2023). ITGB6 expression levels between ICB responders and non-responders were quantified using the ROC Plotter tool (Fekete, 2023), and the figures were generated using Matplotlib in Python. Lung, bladder, head and neck, pancreatic, and cervical cancer all demonstrated high expression of ITGB6. Head and neck squamous cell carcinoma (median fold change 2.70, p<0.0001), bladder urothelial carcinoma (FC 2.41, p<0.001), cholangiocarcinoma (FC 5.33, p<0.01), and esophageal carcinoma (FC 2.72, p<0.03) showed strong upregulation of ITGB6 compared to normal tissue. Interestingly, lung adenocarcinoma (FC 0.77, p<0.04) and lung squamous cell carcinoma (FC 0.55, p<0.0001) showed downregulation of ITGB6 compared to normal tissue. Survival data revealed that ITGB6 was a potent marker of a poor prognosis in pancreatic adenocarcinoma (high ITGB6 median survival 16.79 mos, vs. low ITGB6 21.88 mos, p<0.004) and head and neck squamous cell carcinoma (high ITGB6 30.06 mos vs. low ITGB6 57.42 mos, p<0.03). However, no significant prognostic difference was observed in non-small cell lung cancers. Finally, high pan-cancer expression of ITGB6 led to poorer response to αPD-1 (high ITGB6 Hazard Ratio 1.37, p<0.05) and αPD-L1 (high ITGB6 HR 1.50, p<0.001). In vitro and in vivo experiments to validate the benefit of ITGB6 as a biomarker and as a therapeutic target are underway. Citation Format: William J. MacDonald, Praveen R. Srinivasan, Maximilian Pinho-Schwermann, Vida Tajiknia, Connor Purcell, Lindsey Carlsen, Wafik S. El-Deiry. ITGB6 as a predictive biomarker for overall prognosis and PD-(L)1 immune checkpoint blockade response in various cancer types [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 5140.