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AbstractPurpose: 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. Experimental design: In 2 cohorts of patients with MSI mCRC treated with ICI (exploratory: N=103, validation: N=35), 3’RNAseq was performed from primary tumors. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analysed. Results: In the exploratory cohort, the unsupervised clustering allowed the identification of three clusters of tumors with distinct transcriptional profiles: cluster A (“stromalHIGH-proliferationLOW”), cluster B (“stromalHIGH-proliferationMED”), and cluster C (“stromalLOW-proliferationHIGH”), 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 (pHIGH-proliferationLOW” cluster is associated with a poorer prognosis with ICI treatment.
Gallois et al. (Mon,) studied this question.