Rational discovery of a cancer neoepitope harboring the KRAS G12D driver mutation
| Autor: | John W. Kappler, Hua Bai, Philippa Marrack, Qiuping Zhou, Peng Bai, Sanny K. Chan, Pengcheng Wei, Lei Yin |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
education.field_of_study integumentary system medicine.medical_treatment Population Cancer Immunotherapy Human leukocyte antigen Biology medicine.disease medicine.disease_cause General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis Mutation (genetic algorithm) medicine Cancer research KRAS Allele General Agricultural and Biological Sciences education General Environmental Science Cancer immunology |
| Zdroj: | Science China Life Sciences. 64:2144-2152 |
| ISSN: | 1869-1889 1674-7305 |
| Popis: | Cytotoxic T cells targeting cancer neoantigens harboring driver mutations can lead to durable tumor regression in an HLAI-dependent manner. However, it is difficult to extend the population of patients who are eligible for neoantigen-based immunotherapy, as immunogenic neoantigen-HLA pairs are rarely shared across different patients. Thus, a way to find other human leukocyte antigen (HLA) alleles that can also present a clinically effective neoantigen is needed. Recently, neoantigen-based immunotherapy targeting the KRAS G12D mutation in patients with HLA-C*08:02 has shown effectiveness. In a proof-of-concept study, we proposed a combinatorial strategy (the combination of phylogenetic and structural analyses) to find potential HLA alleles that could also present KRAS G12D neoantigen. Compared to in silico binding prediction, this strategy avoids the uneven accuracy across different HLA alleles. Our findings extend the population of patients who are potentially eligible for immunotherapy targeting the KRAS G12D mutation. Additionally, we provide an alternative way to predict neoantigen-HLA pairs, which maximizes the clinical usage of shared neoantigens. |
| Databáze: | OpenAIRE |
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