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  • The impact of neoantigen vaccines on colorectal cancer treatment

  • Masoume Azad Aza,1,*
    1. Department of Biology, Faculty of Basic Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran


  • Introduction: Colorectal cancer (CRC) is a neoplastic disease of the digestive tract characterized by a gradual onset and an unfavorable prognosis. It ranks as the third most prevalent cancer globally. Cancer is characterized by the uncontrolled proliferation of cells, leading to the formation of tumors. When these aberrantly proliferating cells invade adjacent normal tissues or spread throughout the body, the condition is classified as cancer. Genetic alterations primarily drive the transformation of normal somatic cells into cancerous cells. The heterogeneous nature of these genetic changes, predominantly consisting of mutations, contributes to the complexity of cancer as a disease. Neoantigens are uniquely expressed, enabling them to provoke T-cell responses specific to the tumor, thereby minimizing the risk of unintended damage to non-malignant tissues. These neoantigens are novel epitopes that arise from somatic mutations, offering the potential to bypass T-cell central tolerance to self-epitopes and consequently stimulate immune responses against tumors. Neoantigens represent optimal therapeutic targets due to their capacity to enhance therapeutic specificity, circumvent immune tolerance, and reduce the likelihood of autoimmunity. Consequently, they demonstrate significant efficacy in colorectal cancer treatment.
  • Methods: This study was conducted through extensive searching of databases such as Google Scholar, PubMed, Scopus, and the Web of Science, as well as scientific articles obtained from these platforms. Furthermore, authoritative scientific books and studies published in international congresses were used.
  • Results: The development of colorectal cancer (CRC) primarily involves three signaling pathways: chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylation phenotype (CIMP), that neoantigen can affect them. Tumor antigens can be categorized. Tumour-associated antigens (TAAs) and Tumour-specific antigens (TSAs), are also known as neoantigens. Neoantigens can arise from non-synonymous somatic mutations, including single nucleotide variants (SNVs), insertions and deletions (indels), frameshift mutations, other genomic rearrangements, and post-transcriptional abnormalities. Additionally, neoantigens may be generated through cancer-specific post-translational protein modifications, such as methylation. In colorectal cancer (CRC), small indels are the most prevalent source of neoantigen production. The initial step in developing individualized neoantigen-based therapeutics involves sequencing cancer cells through whole-genome sequencing (WGS). This sequencing aims to identify tumor-specific somatic mutations, which include single nucleotide variants (SNVs), insertions and deletions (indels), fusions, and other forms of genetic variation. Following this, human leukocyte antigen (HLA) typing is conducted, and predictions regarding the interactions between HLA, neoantigens, and T cell receptors (TCRs) are made based on the sequencing data. Subsequently, the mutant peptide is identified by integrating somatic mutations, splicing variants, and HLA binding predictions. Neoantigens produced by frameshift mutations are recognized by the immune system, leading to an effective T-cell response against cancer cells. Antigen-presenting cells (APCs), particularly dendritic cells (DCs), are activated by neoantigens through processes such as phagocytosis. The presence of neoantigens enhances the expression of major histocompatibility complex (MHC) class I and II molecules, as well as co-stimulatory molecules on DCs, a process facilitated by interleukin (IL)-12 and various chemokines. Neoantigens are transported to the endoplasmic reticulum, where they bind to MHC class I molecules and form the T-cell receptor (TCR)-peptide-MHC (pMHC) complex for presentation to T cells. CD8+ T cells recognize neoantigen-loaded DCs, leading to the production of effector and memory T cells, which initiate a robust T-cell immune response. Tumor destruction is mediated by the cytotoxic effects of T cells and the production of cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Neoantigen-specific CD4+ T cells also contribute to anti-tumor immunity by activating DCs and producing cytokines that enhance CD8+ T-cell responses. Additionally, CD4+ T cells can exhibit cytotoxic properties and directly kill tumor cells expressing MHC class II molecules following therapeutic vaccination. Generally, there is a clear role for neoantigens in the immunotherapy of colorectal cancer.
  • Conclusion: The special anti-tumor effects and low incidence of adverse reactions. Adverse events indicate that immunotherapy targeting neoantigens is a significant therapeutic strategy for Neoantigen-based therapy, whether used alone or in combination with other treatments, Other treatment strategies are being utilized in numerous clinical trials, marking the beginning of a new era; however, they will also encounter ongoing challenges.
  • Keywords: organ-specific neoantigen, Vaccines, Colorectal Neoplasms

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