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Finding the True Responders: Stratifying dMMR/MSI-H Tumors for ICI Response
Nari Kim1, Seongwon Na2, Jisung Jang3
1Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea.
Cancers
|January 10, 2026
Summary
A new 20-gene signature identifies immune subgroups in deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) tumors, predicting response to immune checkpoint inhibitors (ICIs). This biomarker improves precision immunotherapy by pinpointing patients likely to benefit from ICI treatment.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immune checkpoint inhibitors (ICIs) are effective in deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) tumors.
- Clinical responses to ICIs in these tumors are variable, necessitating better predictive biomarkers.
Purpose of the Study:
- To define immune subgroups within dMMR/MSI-H tumors.
- To develop a reproducible transcriptomic signature for predicting ICI response.
Main Methods:
- Analysis of four MSI-H-enriched cancer types from The Cancer Genome Atlas (TCGA).
- Stratification of tumors based on immune cell infiltration and T-cell-inflamed gene expression profiles.
- Development and validation of a 20-gene immune signature across multiple cohorts (TCGA, GEO, IMvigor210).
Main Results:
- A 20-gene signature, including CD74, STAT1, TAP1, and HLA genes, demonstrated high reproducibility (mean AUC = 0.95).
- The signature accurately identified tumors with higher PD-L1 blockade response (55.6% vs. 32.8%, p = 0.034) in the IMvigor210 cohort.
- Improved survival trends were observed in the TMB-high subset identified by the signature.
Conclusions:
- The 20-gene signature quantifies immune heterogeneity in dMMR/MSI-H tumors.
- This signature serves as a practical biomarker for identifying ICI responders and guiding precision immunotherapy.
