Cancer Neoantigens: Challenges and Future Directions for Prediction, Prioritization, and Validation

Abstract

Prioritization of immunogenic neoantigens is key to enhancing cancer immunotherapy through the development of personalized vaccines, adoptive T cell therapy, and the prediction of response to immune checkpoint inhibition. Neoantigens are tumor-specific proteins that allow the immune system to recognize and destroy a tumor. Cancer immunotherapies, such as personalized cancer vaccines, adoptive T cell therapy, and immune checkpoint inhibition, rely on an understanding of the patient-specific neoantigen profile in order to guide personalized therapeutic strategies. Genomic approaches to predicting and prioritizing immunogenic neoantigens are rapidly expanding, raising new opportunities to advance these tools and enhance their clinical relevance. Predicting neoantigens requires acquisition of high-quality samples and sequencing data, followed by variant calling and variant annotation. Subsequently, prioritizing which of these neoantigens may elicit a tumor-specific immune response requires application and integration of tools to predict the expression, processing, binding, and recognition potentials of the neoantigen. Finally, improvement of the computational tools is held in constant tension with the availability of datasets with validated immunogenic neoantigens. The goal of this review article is to summarize the current knowledge and limitations in neoantigen prediction, prioritization, and validation and propose future directions that will improve personalized cancer treatment.

Neoantigens: promising targets for cancer therapy

“…177 Neoantigens may now be thoroughly screened across the entire cancer spectrum thanks to the convergence of whole-exome sequencing (WES), RNA-seq, and proteomic data from TCGA. 120,224 However, given the wide variations in tumor types, tumor lesions, and patients, customized immune treatments necessitate the detection and prediction of neoantigens based on distinct patient and tumor characteristics. The identification of genome-expressed mutations as well as details on MHC types of patients are required for the prediction of immunogenic neoantigens, as the sequential stimulation of immune response by tumor neoantigens from mutations depends on several variables, including the translation and processing of peptides, the presentation of the mutated peptides by the MHC molecules and the affinity of the pMHC complexes with the TCRs.…”

Mapping Immune Correlates and Surfaceome Genes in BRAF Mutated Colorectal Cancers

“…All of them belonged to the major histocompatibility complex (MHC) II molecules that are mainly expressed in professional antigen-presenting cells. Antigens presented in these molecules are extra-cellular proteins that are endocytosed and digested in the lysosomes, and those peptide fragments are exposed by the MHC II molecules [ 32 , 33 ]. Of note, high antigen load correlates with an adaptive immune response and, therefore, with a higher efficacy of immune checkpoint inhibitors to be active [ 34 , 35 ].…”

Immunotherapy for Pediatric Acute Lymphoblastic Leukemia: Recent Advances and Future Perspectives

“…Nevertheless, treatment of pediatric ALL by using this promising immunotherapy is absent ( 153 ). Neoantigen, a new mutation-derived protein in tumor cells, is a non-normal cellular product and has proven to be a breakthrough for therapeutic immune targets ( 154 – 157 ). Immunotherapy by harnessing neoepitope-CD8+ T cells to recognize and respond to the neoantigens in pediatric patients with ALL provided us an alternative treatment option ( 158 ).…”