Jung Ho Kim1,2,†, Mi-Kyoung Seo3,4,5,†, Ji Ae Lee1,2, Seung-Yeon Yoo1,2, Hyeon Jeong Oh1,2, Hyundeok Kang3,4, Nam-Yun Cho2, Jeong Mo Bae1,2, Gyeong Hoon Kang1,2,*, Sangwoo Kim3,4,*
1Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
2Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
3Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea
4Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
5Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea
†JHK and M-KS are joint first authors.
*Correspondence to Professor Sangwoo Kim; Professor Gyeong Hoon Kang;
Colorectal cancers (CRCs) with microsatellite instability-high (MSI-H) are hypermutated tumors and are generally regarded as immunogenic. However, their heterogeneous immune responses and underlying molecular characteristics remain largely unexplained.
We conducted a retrospective analysis of 73 primary MSI-H CRC tissues to characterize heterogeneous immune subgroups. Based on combined tumor-infiltrating lymphocyte (TIL) immunoscore and tertiary lymphoid structure (TLS) activity, MSI-H CRCs were classified into immune-high, immune-intermediate, and immune-low subgroups. Of these, the immune-high and immune-low subgroups were further analyzed using whole-exome and transcriptome sequencing.
We found considerable variations in immune parameters between MSI-H CRCs, and immune subgrouping of MSI-H CRCs was performed accordingly. The TIL densities and TLS activities of immune-low MSI-H CRCs were comparable to those of an immune-low or immune-intermediate subgroup of microsatellite-stable CRCs. There were remarkable differences between immune-high and immune-low MSI-H CRCs, including their pathological features (medullary vs mucinous), genomic alterations (tyrosine kinase fusions vs KRAS mutations), and activated signaling pathways (immune-related vs Wnt and Notch signaling), whereas no significant differences were found in tumor mutational burden (TMB) and neoantigen load. The immune-low MSI-H CRCs were subdivided by the consensus molecular subtype (CMS1 vs CMS3) with different gene expression signatures (mesenchymal/stem-like vs epithelial/goblet-like), suggesting distinct immune evasion mechanisms. Angiogenesis and CD200 were identified as potential therapeutic targets in immune-low CMS1 and CMS3 MSI-H CRCs, respectively.
MSI-H CRCs are immunologically heterogeneous, regardless of TMB. The unusual immune-low MSI-H CRCs are characterized by mucinous histology, KRAS mutations, and Wnt/Notch activation, and can be further divided into distinct gene expression subtypes, including CMS4-like CMS1 and CMS3. Our data provide novel insights into precise immunotherapeutic strategies for subtypes of MSI-H tumors.