Abstract Background: Microsatellite instability-high (MSI) is a predictive biomarker for response to immune checkpoint inhibitors (ICI) in metastatic colon adenocarcinoma (COAD), but not all patients respond to ICI. Thus, there is a clinical need to develop novel biomarkers to more accurately predict ICI response in metastatic MSI-COAD. Methods: The transcriptomic subtyping cohort consisted of 793 primary tumor MSI-COAD samples with DNA .05 was considered significant. Results: Clustering of primary MSI-COAD tumor transcriptomes revealed two subtypes that we named “Immune/Stromal” (C1, n=390) and “Goblet/Enterocyte” (C2, n=403). C1 tumors displayed significantly higher proportion of CD8+ T cells, cytolytic scores, and enrichment of EMT, TNFɑ, and IFNɑ/γ;; response gene sets. C2 tumors displayed significantly higher expression of goblet cell and enterocyte marker genes and enrichment of metabolic gene sets. LOF mutations in epigenetic regulators ARID1A, ARID1B, and EP300 were enriched in C1 tumors. In the ICI cohort of metastatic MSI-COAD patients, C2 was associated with significantly shorter PFS (HR = 6.6, 95% CI: 2.2-19.6, p 0.0001) and OS (HR = 4.4, 95% CI: 1.4-13.3, p 0.001). In C2 patients, the median PFS and OS following ICI were 8 and 34 months, respectively; in C1, neither median was reached. C2’s association with shorter PFS but not OS following ICI was independent of ICI regimen, line of therapy, collection procedure type, age, sex, and TMB in a CoxPH model (HR = 7.0, 95% CI: 1.8-26.6, p = 0.005). In the subset of our ICI cohort treated with Nivolumab + Ipililumab (n=10), we observed that 4/4 C2 patients progressed within 6 months of treatment while 0/6 C1 patients progressed (p = 0.049, HR = Inf). Finally, we demonstrate that NMF subtypes presented here have a stronger association with PFS in CoxPH models following ICI compared to CMS subtypes (CMS3 vs CMS1 HR=3.5, 95% CI: 1.1-11.1, p = 0.04, CMS4 vs CMS1 HR = 4.2, 95% CI: 0.7-24.6, p = 0.11). Conclusions: We identified novel MSI-COAD transcriptomic subtypes that stratify patient response to ICI, including Nivolumab + Ipililumab. In addition to personalizing patient care, these subtypes could inform clinical trial design and target discovery by identifying patients with an unmet clinical need. Acknowledgements We acknowledge FightCRC for funding this study and colleagues at Tempus AI and FightCRC for helpful discussion. Citation Format: Matthew B. Maxwell, Akul Singhania, Michelle Stein, Radia Johnson, Van K. Morris, Andrew J. Sedgewick, Scott Kopetz, Justin Guinney. MSI colon adenocarcinoma transcriptomic subtypes are biomarkers of response to immunotherapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5337.
Maxwell et al. (Fri,) studied this question.