Abstract P16: Characterisation of the MSS-CRC surface proteome for novel immunotherapeutic target discovery

Abstract The integral role of cell-surface proteins as key communicators and interactors with the external environment can orchestrate cancer initiation and progression. Consequently, the tumour surface proteome (‘surfaceome’) is often remodelled during tumorigenesis and metastasis, representing an abundant resource for potential immunotherapeutic target discovery. Microsatellite-stable colorectal cancer (MSS-CRC) is notorious for its immunosuppressive tumour microenvironment and poor efficacy towards existing single-arm and combinations of immunotherapies. With a paucity of immune-druggable surface targets, we focused on deconvoluting the MSS-CRC ‘surfaceome’ for novel immunotherapeutic target identification. Here, we performed extracellular biotinylation of MSS-CRC patient-derived organoids, and quantitative proteomics on affinity-enriched membrane proteins, comparing healthy, primary and metastatic MSS-CRC. From a total pool of 487 highly confident surface proteins, we first demonstrate the reliability and clinical relevance of our dataset through the detection of high levels of prominent CRC progression markers CDH17, LY75 and CA9. Importantly, we shortlisted 2 potential targets DPEP1 and SCARB1 which displayed differentially upregulated protein expression in primary MSS-CRC and further validated using tissue microarray and gene silencing approaches. In this clinically relevant dataset, we also unveil a novel MSS-CRC progression marker, ITGB8, which showed sequential downregulation from healthy to metastatic MSS-CRC. The discovery of these MSS-CRC-specific targets and progression markers holds promise in elucidating underlying molecular mechanisms driving MSS-CRC. Ultimately, we aim to progress targeted therapeutic approaches in MSS-CRC which culminates in the construction of a therapeutic decision tree for precise clinical intervention selection tailored to each MSS-CRC patient. Citation Format: Daryl Chin, Ziliang Ma, Wei Wu. Characterisation of the MSS-CRC surface proteome for novel immunotherapeutic target discovery abstract. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85 (15Suppl): Abstract nr P16.