Abstract
mRNA vaccines have become a promising alternative to conventional cancer immunotherapy approaches. However, its application on colorectal cancer (CRC) remains poorly understood. We herein identified potential antigens for designing an effective mRNA vaccine, further to build an immune landscape for the accurate selection of patients for mRNA vaccine therapy. Raw transcriptome data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were retrieved. Consensus clustering algorithm was applied to divide the CRC samples into four immune subtypes. Immunogenomics analysis was further integrated to characterize the immune microenvironment of each immune subtype. Six tumor antigens were found to be associated with poor prognosis and infiltration of antigen-presenting cells (APCs) in CRC patients. Furthermore, each of the immune subtypes showed differential cellular and molecular features. The IS2 and IS4 exhibited significantly improved survival and higher immune cell infiltration compared with IS1 and IS3. Immune checkpoint molecules and human leukocyte antigen also showed significant differential expression in four immune subtypes. Moreover, we performed graph structure learning-based dimensionality reduction to visualize the immune landscape of CRC. Our results revealed a complex immune landscape that may provide directions for mRNA vaccine treatment of CRC and define appropriate vaccination patients.
Highlights
Colorectal cancer (CRC) is the third most frequently diagnosed tumor, with the second highest mortality rate worldwide (Sung et al, 2021)
Mutational analysis showed that the adenomatous polyposis coli (APC), tumor suppressor P53 (TP53), KRAS proto-oncogene GTPase (KARS), titin (TTN), spectrin repeat containing nuclear envelope protein 1 (SYNE1), mucin 16 (MUC16), and low-density lipoprotein receptor-related protein 1B (LRP1B) were the most frequently mutated genes in the fraction genome alteration and tumor mutational count group (Figures 1D,E)
We investigated whether the expression of thrombospondin 2 (THBS2), follistatin like 3 (FSTL3), troponin T1 (TNNT1), BGN, collagen triple helix repeat containing 1 (CTHRC1), and NADPH oxidase 4 (NOX4) was correlated with immune cell infiltration levels in colorectal cancer (CRC) via the Tumor Immune Estimation Resource (TIMER) database
Summary
Colorectal cancer (CRC) is the third most frequently diagnosed tumor, with the second highest mortality rate worldwide (Sung et al, 2021). Compared with the currently available drugs, the mRNAbased approach has a number of advantages: 1) mRNA is produced and purified in vitro, without any need of the complex process of protein drug and viral vector preparation; 2) IVT mRNA production process is highly versatile. Clinical trials have demonstrated that the protein expression of mRNA is transient, it is effective for tumor immunotherapy applications. MRNA vaccines have been applied to treat solid tumors, including non-small cell lung cancers, melanoma, prostate cancer, and glioblastoma (Sebastian et al, 2014; Kubler et al, 2015; Papachristofilou et al, 2019; Batich et al, 2020). A great deal of clinical trials has been started and consistently verified the feasibility and suitability of mRNA vaccines for cancer treatment
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