Abstract 3617: Immunogenomic alterations driving premalignant lesions to invasive lesions of the head and neck

Abstract Head and neck squamous cell carcinoma (HNSCC) is the seventh most prevalent type of cancer globally with 940,000 new cases and 480,000 fatalities yearly. Oral squamous cell carcinoma (OSCC) is characterized by molecular alterations that drive progression of some preneoplastic lesions to invasive cancer. Not all dysplastic premalignant lesions evolve into carcinoma in situ or full-blown carcinoma. Moreover, this transition may occur as these lesions evolve over years. Identifying precancerous lesions likely to progress to invasive cancer remains challenging. Comprehensive immunogenomic profiling may reveal whether immune tolerance is a hallmark of early dysplasia and/or an acquired prerequisite for malignant transformation. We thus conducted a longitudinal study with matched dysplastic and invasive lesions to uncover early molecular drivers, reveal clonal relationships, and to identify genomic and immune mechanisms underlying SCC progression. Samples were obtained from The Ohio State University (OSU) and The Johns Hopkins University (JH). RNA was extracted from a total of 111 FFPE samples from 34 patients with precursor lesions and/or HNSCC across different stages (OSU) and submitted for RNA sequencing. Differential gene expression analysis was performed in invasive versus dysplastic lesions. Immune-related transcripts were annotated by curated immune gene sets to characterize microenvironmental remodelling. To investigate the interactions between tumor and immune cells at the subcellular resolution, spatial transcriptomics of matched dysplasia and invasive SCC was performed in a subset of patients using 10X Genomics Visium HD platform followed by Seurat based downstream analysis. For tumor-immune interaction analysis, we integrated spatial data with a single-cell reference atlas containing annotated immune cell subtypes and tumor cell states. Bulk RNA-seq revealed 164 differentially expressed genes in invasive versus dysplastic lesion, with enrichment in extracellular matrix remodelling, epithelial-mesenchymal transition and cytokine signalling pathways. Moreover, 80% of immune genes (e.g. CXCL9/10, CCL5, STAT1) are upregulated in invasive SCC. Preliminary spatial transcriptomics data revealed distinct immune microenvironments between invasive and dysplastic regions, with enrichment of immune cells at the tumor-stroma interface. The current comparative analysis revealed distinct immune infiltration patterns between dysplastic and invasive lesions, suggesting the spatial evolution of immune evasion mechanisms during cancer progression. Our cohort of samples is unique with paired patient samples that progressed from a biopsy proven premalignant state to invasive cancer over time. Our preliminary data suggest that we can identify premalignant lesions likely to progress and targetable immunogenomic drivers to intercept cancer progression at an earliest stage. Citation Format: Foram Ujjvalkumar Vaidya, Alvaro Gutierrez, Abberly Lott Limbach, Bhavna Kumar, Martin P. Alphonse, James W. Rocco, Mariana Brait, Amanda Ewart Toland, David Sidransky. Immunogenomic alterations driving premalignant lesions to invasive lesions of the head and neck abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3617.