Transcriptomic Signatures of MSI-high Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors

Microsatellite instability (MSI) is currently the only biomarker predictive of immunotherapy efficacy in patients with metastatic colorectal cancer (mCRC). However, 10-40% of patients with MSI mRCC will experience primary resistance to immunotherapy.

The work of C. Gallois et al (team 1), recently published in Clinical Cancer Research, has identified MSI CRC patients at risk of resistance to immunotherapy. Using previously published single-cell data, transcriptomic signatures of the tumor microenvironment were analyzed in 2 independent cohorts of 103 and 35 MSI CRC patients treated with immunotherapy. Three groups of patients with distinct transcriptional profiles reflecting different MET cell compositions and MET/tumor cell proliferative capacities were identified:

– group A (“stromalHIGH-proliferationLOW” )
– group B (“stromalHIGH-proliferationMED” )
– group C (“stromalLOW -proliferationHIGH”)

Results showed a higher proportion of primary progression, significantly shorter progression-free survival and overall survival under immunotherapy in patients belonging to group A, compared with those belonging to groups B and C. In contrast, group A was not associated with poorer outcomes in patients treated with conventional chemotherapy.

This classification could therefore help identify patients with MSI mRCC at risk of resistance to immunotherapy, in whom the therapeutic strategy could be adapted.

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