Genomic and transcriptomic characterization of heterogeneous immune subgroups of microsatellite instability-high colorectal cancers

Abstract

BackgroundColorectal 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.MethodsWe 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.ResultsWe 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.ConclusionsMSI-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.

Multi‐omics analysis of the oncogenic value of copper Metabolism‐Related protein COMMD2 in human cancers

“…TMB was found to be favorably connected with COMMD2 expression in CHOL, LUAD, BLCA, and GBM, but negatively in case of ESCA, mesothelioma (MESO), and diffuse large B‐cell lymphoma (DLBC) (Figure 7A). MSI is mainly caused by the absence of DNA mismatch repair systems, and it can be used to forecast the prognosis of the tumor and the effectiveness of immunotherapy 34 . In rectal adenocarcinoma (READ), TGCT, STAD, UCEC, and BLCA, COMMD2 expression was positively correlated with MSI; however, COMMD2 had an adverse relationship with MSI in DLBC, KICH, and LUSC (Figure 7B).…”

Clinical Significance and Immune Infiltration Analyses of the Cuproptosis-Related Human Copper Proteome in Gastric Cancer

“…We collected information on MSI, TMB and CBPscores. TMB and MSI-H are classic biomarkers to predict response for immunotherapy as neoantigen burden, which induces anti-tumor immune responses and is always increased by TMB and MSI-H [ 38 , 39 , 40 , 41 ]. Collectively, patients with high levels of TMB and MSI had a low CBP signature, which is useful for T cell recognition [ 42 ].…”

The Role of Interleukin-7 in the Formation of Tertiary Lymphoid Structures and Their Prognostic Value in Gastrointestinal Cancers

“… 48 The size of TLSs that formed in these tumors was evaluated and scored as having high or low TLS activity, with higher TLS activity reflecting larger TLS formation on average as measured by an established histomorphometric method. 49 Average TLS activity score was found to be higher in MSI-H CRC tumors, although there was much more variability in both TLS activity score and infiltration of CD8 + tumor-infiltrating lymphocytes (TIL) than in MSS tumors. 49 This increased variability could explain why response rates to CPIs remains limited in MSI-H tumors.…”

“… 49 Average TLS activity score was found to be higher in MSI-H CRC tumors, although there was much more variability in both TLS activity score and infiltration of CD8 + tumor-infiltrating lymphocytes (TIL) than in MSS tumors. 49 This increased variability could explain why response rates to CPIs remains limited in MSI-H tumors. 50 CRC tumors also have peritumoral lymphoid aggregates referred to as Crohn's-like lymphoid reaction (CLR), which despite its name, has no known relationship with Crohn's disease and can be considered a type of TLS specific to CRC.…”