Transcriptomic signatures of MSI-high metastatic colorectal cancer to predict efficacy of immune checkpoint inhibitors

3570 Background: Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10-40% of patients with MSI mCRC will experience a primary resistance to ICI. Methods: In a cohort of 103 patients with MSI mCRC treated with ICI, 3’RNAseq was performed from primary tumors resected before the beginning of ICI. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analysed. Results: The unsupervised clustering of this cohort allowed the identification of three clusters of tumors with distinct transcriptional profiles: cluster A (“stromal HIGH -proliferation LOW ”), cluster B (“stromal HIGH -proliferation MED ”), and cluster C (“stromal LOW -proliferation HIGH ”), with an enrichment of patients progressing at first disease assessment under ICI in the cluster A (30% vs 12% in cluster B and 8.1% in cluster C, p = 0.074). Progression-free survival (PFS) was also significantly shorter in patients belonging to cluster A, compared to clusters B or C (p < 0.001) with 2-year PFS rates of 33.5%, 80.5% and 78.3%, respectively. Similar results were observed for overall survival (OS).In multivariate analysis, PFS was still significantly longer in patients belonging to cluster B (HR: 0.26 95%CI 0.11-0.58, p = 0.001) and cluster C (HR: 0.35 95%CI 0.16-0.78, p = 0.01), compared to patients belonging to cluster A (Table). No association of identified clusters with PFS during non-ICI-based regimens was identified. Conclusions: This unsupervised transcriptomic classification identified three groups of MSI mCRCs with different compositions of TME cells and proliferative capacities of TME/tumor cells. The “stromal HIGH -proliferation LOW ” cluster is associated with a lower efficacy of ICI. [Table: see text]