Abstract
Recent preclinical and clinical studies have proved the long-standing hypothesis that tumors elicit adaptive immune responses and that the antigens driving effective T-cell response are neoantigens, i.e., peptides that are generated from somatically mutated genes. Hence, the characterization of neoantigens and the identification of the immunogenic ones are of utmost importance for improving cancer immunotherapy and broadening its efficacy to a larger fraction of patients. In this review, we first introduce the methods used for the quantification of neoantigens using next-generation sequencing data and then summarize results obtained using these tools to characterize the neoantigen landscape in solid cancers. We then discuss the importance of neoantigens for cancer immunotherapy using checkpoint blockers, vaccination, and adoptive T-cell transfer. Finally, we give an overview over emerging aspects in cancer immunity, including tumor heterogeneity and immunoediting, and give an outlook on future prospects.
Highlights
In the past decade, driven by technological advances major progress in cancer research and cancer therapy was made
These mutated neoantigens, which are present in the malignant cells but not in the normal cells can be recognized as foreign by tumor-infiltrating lymphocytes (TILs) and elicit potent tumorspecific immune responses
Since T cells recognizing neoantigens are not influenced by central immune tolerance because of the lack of expression in healthy tissues, targeting of tumor neoantigens may be more specific and less toxic than other approaches, making neoantigens attractive targets for immunotherapy, including therapy with antibodies directed against immune checkpoint blockers, therapeutic vaccination, or adoptive T-cell transfer with T-cell receptors (TCR)-engineered neoantigenspecific T cells
Summary
Driven by technological advances major progress in cancer research and cancer therapy was made. Novel drugs targeting immune checkpoint molecules have been approved in several malignancies and are showing remarkable clinical effects These drugs augment T-cell activity by blocking cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), or PD-1 ligand. Antigens with high tumoral specificity have the potential to elicit tumorspecific immune responses and are, of great interest for cancer immunotherapeutic strategies, including therapeutic vaccines and engineered T cells. Mutated proteins are proteolytically cleaved into short peptides and presented on the tumor cell surface by the MHC—called human leukocyte antigen (HLA) in humans These mutated neoantigens, which are present in the malignant cells but not in the normal cells can be recognized as foreign by tumor-infiltrating lymphocytes (TILs) and elicit potent tumorspecific immune responses. We give an overview of the current advances in the computational prediction of neoantigens and discuss the development of cancer immunotherapies targeting neoantigens, including vaccination, checkpoint therapy, and adoptive cell transfer
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