A common cancer where MSI status determines immunotherapy eligibility–and where functional biomarkers could expand access.
Colorectal cancer illustrates the biomarker stratification paradigm. MSILoading...-H CRC responds dramatically to checkpoint blockade–pembrolizumab is now first-line for metastatic MSI-H CRC, outperforming chemotherapy. But MSS CRC, despite often expressing PD-L1, shows minimal ICILoading... response.
This divide reflects biology: MSI-H tumors are hypermutated and immunogenic; MSS tumors have fewer neoantigens and use other immune evasion mechanisms.
Two Types: About 15% of colorectal cancers have "microsatellite instability" (MSI-high)—these respond well to immunotherapy. The other 85% (MSS) generally don't respond.
Current Testing: MSI status is routinely tested. MSI-high patients receive checkpoint inhibitors.
The challenge is identifying MSS CRC patients who might still benefit from immunotherapy. Combinations with targeted agents, radiation, or ablation are under investigation. The hypothesis: inducing immunogenic cell death might sensitize MSS tumors.
The 2022 iFRET study of post-RFALoading... lung metastases demonstrated that checkpoint engagement changes after ablation–even in MSS tumors. This suggests functional biomarkers could identify MSS patients whose tumors become immunotherapy-responsive after combination treatment.
The Challenge: MSS colorectal cancers have lower mutation rates and are considered "cold" immunologically. But some might still benefit from immunotherapy.
The Opportunity: Functional checkpoint measurement could potentially identify MSS patients who have active checkpoint engagement and might respond to immunotherapy.
Clinical Evidence: CRC lung metastases provided tissue for validating both CTLA-4/CD80 and PD-1/PD-L1 iFRET quantification (2022[4]). The study demonstrated that checkpoint expression did not correlate with interaction state–confirming the functional biomarker principle in CRC.
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CRC evidence: Colorectal cancer lung metastases validated both checkpoint assays. Key finding: expression did not correlate with interaction–the functional biomarker principle confirmed in CRC.
