Integrin-D6 Modulates the Tumor Microenvironment q and Serves as a Prognostic Marker in Lung Squamous Cell Carcinoma

Document Type

Conference Proceeding

Publication Date

10-1-2025

Publication Title

J Thorac Oncol

Keywords

antibody drug conjugate, beta6 integrin, biological marker, collagen, integrin, sigvotatug vedotin, vedotin, adult, aged, algorithm, cancer associated fibroblast, CD4+ T lymphocyte, cell infiltration, clinical article, cohort analysis, conference abstract, controlled study, deconvolution, deconvolution algorithm, dendritic cell, differential gene expression, drug therapy, epithelial mesenchymal transition, epithelium cell, extracellular matrix, female, gene set enrichment analysis, human, human cell, human tissue, immunocompetent cell, lung epithelium, lung fibroblast, M1 macrophage, M2 macrophage, male, microenvironment, monocyte, non small cell lung cancer, overall survival, protein analysis, protein expression, regulatory T lymphocyte, RNA sequencing, single cell analysis, single cell RNA seq, squamous cell lung carcinoma, tumor growth, tumor microenvironment, upregulation

Abstract

Introduction: Integrin-^6 (ITGB6) is a member of the integrin family implicated in tumor proliferation and metastasis in non-small cell lung cancer (NSCLC), making it a compelling therapeutic target. Interest in ITGB6 has recently grown with the development of sigvotatug vedotin, an ITGB6-targeted antibody-drug conjugate (ADC) conjugated to monomethyl auristatin E (MMAE), which has shown promising effi cacy in heavily pretreated NSCLC. In this analysis, we investigate the prognostic relevance of ITGB6 expression and its impact on the tumor microenvironment (TME) in lung squamous cell carcinoma (LUSC). Methods: We analyzed bulk RNA sequencing data from the TCGALUSC cohort and single-cell RNA-seq data from GSE131907, GSE148071, and GSE162498. ITGB6 RNA and protein expression in tumor vs. normal tissues were evaluated using GEPIA2 and UALCAN, respectively. Differential gene expression between high (top 25%, n =135) and low (bottom 25%, n =135) ITGB6 expressors was performed using DESeq2. Immune cell infiltration was assessed via XCell and EPIC deconvolution algorithms. Gene set enrichment analysis (GSEA) was conducted using Enrichr. Single-cell data were processed in Seurat following standard QC and normalization workflows. Cor relation analyses were performed using the CSCORE algorithm. Prognostic value was assessed using a multivariate Cox regression model adjusting for stage, age, and gender. Results: The TCGA-LUSC cohort included 512 patients with full transcriptomic and survival data. Patients with higher ITGB6 expression, stratified by median expression level, had worse overall survival (OS) compared to those with lower expression (logrank p = 0.0019). Moreover, a multivariate Cox regression for OS confirmed high ITGB6 expression as an independent predictor of poor prognosis (HR = 1.39, P = 0.0201). Bulk RNA and protein analysis revealed no significant difference in ITGB6 expression between tumor and normal samples. However, single-cell analysis demonstrated significantly lower ITGB6 expression in ma lignant LUSC epithelial cells compared to normal lung epithelium (log2FC = -0.96, P < 0.0001). High ITGB6 expressors showed upregulation of genes involved in epithelial-to-mesenchymal transition (EMT) and cancer-associated fibroblast (CAF) activation, including ANGPTL4, FN1, FAP, VIM, and CAV1. GSEA revealed enrichment in pathways such as EMT, extracellular matrix (ECM) organization, CXCR chemokine receptor binding, and collagen remodeling. Immune deconvolution showed that high ITGB6 expression was associated with increased infiltration of CAFs, dendritic cells, monocytes, M1 and M2 macrophages, T regulatory cells, and higher immune and microenvironment scores. Conversely, infiltration of Th1 and Th2 CD4+ T cells was reduced (all p < 0.01). Single-cell analysis further revealed elevated ITGB6 expression in CAFs from LUSC tumors compared to normal lung fibroblasts (log2FC = 1.97, P < 0.0001). Conclusions: High ITGB6 expression is an independent poor prognostic marker of OS in LUSC and is associated with an immunosuppressive and fibrotic TME characterized by active CAFs and increased ECM remodeling. These findings suggest that ITGB6 may not only serve as a therapeutic target but also as a biomarker for patient stratification in LUSC, particularly in the context of ADC therapy.

Volume

20

Issue

10

First Page

S319

Find It @ Sladen

Share

COinS