The KRAS-Mutant Consensus Molecular Subtype 3 Reveals an Immunosuppressive Tumor Microenvironment in Colorectal Cancer

Abstract

Colorectal cancers (CRC) with KRAS mutations (KRASmut) are frequently included in consensus molecular subtype 3 (CMS3) with profound metabolic deregulation. We explored the transcriptomic impact of KRASmut, focusing on the tumor microenvironment (TME) and pathways beyond metabolic deregulation. The status of KRASmut in patients with CRC was investigated and overall survival (OS) was compared with wild-type KRAS (KRASwt). Next, we identified CMS, and further investigated differentially expressed genes (DEG) of KRASmut and distinctive pathways. Lastly, we used spatially resolved gene expression profiling to define the effect of KRASmut in the TME regions of CMS3-classified CRC tissues. CRC patients with KRASmut were mainly enriched in CMS3. Their specific enrichments of immune gene signatures in immunosuppressive TME were associated with worse OS. Activation of TGFβ signaling by KRASmut was related to reduced pro-inflammatory and cytokine gene signatures, leading to suppression of immune infiltration. Digital spatial profiling in TME regions of KRASmut CMS3-classified tissues suggested up-regulated genes, CD40, CTLA4, ARG1, STAT3, IDO, and CD274, that could be characteristic of immune suppression in TME. This study may help to depict the complex transcriptomic profile of KRASmut in immunosuppressive TME. Future studies and clinical trials in CRC patients with KRASmut should consider these transcriptional landscapes.

Mesothelin expression correlates with elevated inhibitory immune activity in patients with colorectal cancer

“…Regarding gene mutation patterns, recent studies have determined that increased mutation in KRAS and FBXW7 have been implicated as immunosuppressive biomarkers that play a role in poor immunotherapeutic responses in CRC. 43 , 44 Additionally, high co-expression of HAVCR2 and MSLN have been shown to be prevalent in several cancers and may also be vulnerabole to the use of CAR-T therapies. Pre-clinical studies have shown the utility of CAR-T therapy in an MSLN high ovarian cancer model.…”

Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment

“…Molecular testing for activating KRAS and NRAS mutations (comprehensive RAS panel) and BRAF mutations is recommended by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) to select patients for anti-EGFR therapy [ 23 ]. Activating mutations in KRAS may also contribute to an immunosuppressive tumor microenvironment [ 24 ] and the lack of response of mCRC originating via the CIN pathway rather than the MSI pathway. Direct pharmacological targeting of mutated KRAS was not possible until recently, and drugs for KRAS mutations common in mCRC (e.g., KRAS G12D ) are not yet clinically validated.…”

Associations of Multiparametric Breast MRI Features, Tumor-Infiltrating Lymphocytes, and Immune Gene Signature Scores Following a Single Dose of Trastuzumab in HER2-Positive Early-Stage Breast Cancer

“…Immune signature scores were obtained through a commercially available service (Nanostring, Seattle, WA, USA) using the Nanostring PanCancer IO360 panel as previously described [23]. Briefly, samples were submitted to Nanostring for gene expression profiling using the nCounter analysis system.…”

“…Raw data were analyzed using nSolver Analysis Software through the IO 360 Data Analysis Service (Nanostring, Seattle, WA, USA). Differential gene expression and hierarchical clustering were performed as previously described [23].…”