The role of neoantigen in immune checkpoint blockade therapy

Abstract

Immune checkpoint inhibitor induces tumor rejection by activated host immune system. The anti-tumor immune response consists of capture, presentation, recognition of neoantigen, as well as subsequent killing of tumor cell. Due to the interdependence among this series of stepwise events, neoantigen profoundly influences the efficacy of anti-immune checkpoint therapy. Moreover, the neoantigen-specific T cell reactivity is the cornerstone of multiple immunotherapies. In fact, several strategies targeting neoantigen have been attempted for synergetic effect with immune checkpoint inhibitor. Increasing neoantigen presentation to immune system by oncolytic virus, radiotherapy, or cancer vaccine is feasible to enhance neoantigen-specific T cell reactivity in theory. However, some obstacles have not been overcome in practice such as dynamic variation of neoantigen landscape, identification of potential neoantigen, maintenance of high T cell titer post vaccination. In addition, adoptive T cell transfer is another approach to enhance neoantigen-specific T cell reactivity, especially for patients with severe immunosuppression. In this review, we highlighted the advancements of neoantigen and innovative explorations of utilization of neoantigen repertoire in immune checkpoint blockade therapy.

Keywords: Adoptive T cell transfer; CTLA-4; Cancer vaccine; Immunotherapy; Neoantigen; PD-1/PD-L1.

Fig. 1

Cancer-Immunity cycle and neoantigen presentation. cancer-immunity cycle: neoantigen released by dead cancer cell initiates the anti-tumor immune response. Then the neoantigen is captured and presented by antigen presentation cell (APC) which induces the priming and activation of neoantigen-specific T cell in peripheral immune organ. Peripheral activated T effector cell traffics to and infiltrates into tumor bed. Following recognition of neoantigen, tumor cell is killed by tumor infiltrating lymphocyte (TIL). Neoantigen presentation: in the proteasome of tumor cell, mutant protein derived from somatic mutation is degenerated into peptide and then transported to endoplasmic reticulum. The peptide binds to major histocompatibility complex I (MHC-I) binding site by transporter associated with antigen processing (TAP). Simultaneously, the assembled peptide-MHC-I complex is transported to membrane of tumor cell. Cytotoxic T cell could recognize peptide-MHC-I complex and kill the tumor cell

Fig. 2

The number of mutant gene across 29 types of tumor. Average mutant gene number is calculated based on TCGA datasets (https://tcga.xenahubs.net). ACC adrenocortical cancer, BLCA bladder cancer, CESC cervical cancer, CHOL cholangiocarcinoma, COAD colon adenocarcinoma, DLBC lymphoid neoplasm diffuse large B-cell lymphoma, ESCA esophageal carcinoma, GBM glioblastoma multiforme, HNSC head & neck squamous cell carcinoma, KICH kidney chromophobe cancer, KIRC Kidney renal clear cell carcinoma, KIRP kidney papillary cell carcinoma, LAML acute myeloid leukemia, LIHC hepatocellular carcinoma, LUAD lung adenocarcinoma, LUSC lung squamous cell carcinoma, MESO mesothelioma, OV ovarian serous cystadenocarcinoma, PAAD pancreatic adenocarcinoma, PRAD prostate adenocarcinoma, READ rectal cancer, SARC sarcoma, SKCM melanoma, STAD stomach adenocarcinoma, TGCT testicular germ cell tumor, THCA thyroid cancer, THYM thymoma, UCEC endometrioid cancer, UCS uterine carcinosarcoma

Fig. 3

Prediction of candidate neoantigen. The common prediction algorithm consists of three parts: a identification of mutated protein; b identification of major histocompatibility complex (MHC) typing; c prediction of the binding affinity between MHC and neo-peptides