Abstract 6466: Discovery Proteome and Whole Transcriptome Atlas analysis of skin cancer reveals biomarkers associated with immunotherapy response and resistance

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and represents a major global health burden. Approximately 50% of cSCC patients develop primary resistance and 20% will develop secondary resistance to immune checkpoint inhibitors (ICI). There are limited biomarkers that reflect the tumor dynamics predictive of response to ICI therapy and we need to develop a better understanding of the cSCC tumor microenvironment (TME). Enabling simultaneous analyses of proteins and RNAs at ultra-high plex in spatial context, the GeoMx Digital Spatial Profiler (DSP) offers an advanced same slide multiomics workflow and is uniquely positioned to help unravel cellular dynamics throughout the cSCC TME. In this study, we spatially profiled over 1000 proteins (GeoMx Human Discovery Proteome Atlas (DPA)) and over 18,000 transcripts (GeoMx Whole Transcriptome Atlas) using the DSP on formalin fixed paraffin embedded sections of pre-treatment cutaneous skin cancers prior to immunotherapy. Pathology-informed, tumour and stromal regions were sampled across whole tissues to generate histologically relevant assessments of the skin tissues. Covering areas such as immuno-oncology, oncology, immunology, epigenetics, metabolism, cell death, and signaling pathway regulation, the DPA panel supported the discovery of biomarkers and potential therapeutic targets. Our study identified unique tumour and stromal signatures and biomarkers associated with both resistance and sensitivity to immunotherapy at both protein and RNA resolutions. Moreover, coverage across the protein hallmarks of cancer provided deeper insights into the tumour microenvironment dictating clinical responses to therapy. Our study provides an integrated pipeline for discovery based spatial proteomic and transcriptomic assessments of skin cancers. Citation Format: Arutha Kulasinghe, Christine Kang, Hiromi Sato, Brian Filanoski, Lori Hamanishi, Ashley Heck, Margaret Hoang, Alyssa Rosenbloom, Michael Rhodes, Joseph M. Beechem. Discovery Proteome and Whole Transcriptome Atlas analysis of skin cancer reveals biomarkers associated with immunotherapy response and resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6466.