Neoantigens and their potential applications in tumor immunotherapy

Abstract

The incidence of malignant tumors is increasing, the majority of which are associated with high morbidity and mortality rates worldwide. The traditional treatment method for malignant tumors is surgery, coupled with radiotherapy or chemotherapy. However, these therapeutic strategies are frequently accompanied with adverse side effects. Over recent decades, tumor immunotherapy shown promise in demonstrating notable efficacy for the treatment of cancer. With the development of sequencing technology and bioinformatics algorithms, neoantigens have become compelling targets for cancer immunotherapy due to high levels of immunogenicity. In addition, neoantigen-based vaccines have demonstrated potential for cancer therapy, primarily by augmenting T-cell responses. Neoantigens have also been shown to be effective in immune checkpoint blockade therapy. Therefore, neoantigens may serve to be predictive biomarkers and synergistic treatment targets in cancer immunotherapy. The aim of the present review was to provide an overview of the recent progress in the classification, screening and clinical application of neoantigens for cancer therapy.

Keywords: immune checkpoint blockade; immunotherapy; neoantigen; tumor vaccine.

Figure 1.

Stages of cancer-immunity cycle. Necrotic tumor cell antigens are released and captured by DCs. DCs present the captured antigens to T cells, resulting in the activation of effector T cells. The activated effector T cells then recognize and bind to cancer cells. Tumor cells killed by T cells in turn release antigens that enter the immune cycle again to amplify the response in subsequent revolutions of the cycle. DCs, Dendritic cells; CTLA-4, cytotoxic T lymphocyte protein 4; PD-L1, programmed-death ligand 1.

Figure 2.

MHC-I antigen complex formation. After DCs ingest antigen precursors, the polypeptides are fragmented and transported into the ER for further editing. The processed peptides then encounter MHC-I molecules within the PLC as well as ERAAP. When the MHC-I complex reaches a certain stability threshold, it leaves the ER and reaches the cell surface for antigen presentation. MHC, major histocompatibility complex; DCs, dendritic cells; ER, endoplasmic reticulum; PLC, peptide-loading complex; ERAAP, endoplasmic reticulum aminopeptidase related to antigen processing.

Figure 3.

Schematic illustration of the neoantigen screening and clinical application workflow. WES is typically performed on tumor and normal DNA to identify tumor-specific mutations. Next, a computer algorithm is used to predict the affinity of neoantigen peptides to HLA-1 molecules. The immunological effects of candidate neoantigens were then evaluated as to whether they could be recognized by autologous T cells. Finally, the immunotherapies, including neoantigen vaccines, ACT based on neoantigens or combination therapies with checkpoint inhibitors are applied in the clinic. HLA, leukocyte antigen; WES, whole-exome sequencing; ACT, adoptive cellular immunotherapy.