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Breast Cancer Neoantigens Can Induce CD8+ T-Cell Responses and Antitumor Immunity.

ABSTRACT: Next-generation sequencing technologies have provided insights into the biology and mutational landscape of cancer. Here, we evaluate the relevance of cancer neoantigens in human breast cancers. Using patient-derived xenografts from three patients with advanced breast cancer (xenografts were designated as WHIM30, WHIM35, and WHIM37), we sequenced exomes of tumor and patient-matched normal cells. We identified 2,091 (WHIM30), 354 (WHIM35), and 235 (WHIM37) nonsynonymous somatic mutations. A computational analysis identified and prioritized HLA class I-restricted candidate neoantigens expressed in the dominant tumor clone. Each candidate neoantigen was evaluated using peptide-binding assays, T-cell cultures that measure the ability of CD8+ T cells to recognize candidate neoantigens, and preclinical models in which we measured antitumor immunity. Our results demonstrate that breast cancer neoantigens can be recognized by the immune system, and that human CD8+ T cells enriched for prioritized breast cancer neoantigens were able to protect mice from tumor challenge with autologous patient-derived xenografts. We conclude that next-generation sequencing and epitope-prediction strategies can identify and prioritize candidate neoantigens for immune targeting in breast cancer. Cancer Immunol Res; 5(7); 516-23. ©2017 AACR.

SUBMITTER: Zhang X

PROVIDER: S-EPMC5647648 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Breast Cancer Neoantigens Can Induce CD8<sup>+</sup> T-Cell Responses and Antitumor Immunity.

Zhang Xiuli X Kim Samuel S Hundal Jasreet J Herndon John M JM Li Shunqiang S Petti Allegra A AA Soysal Savas D SD Li Lijin L McLellan Mike D MD Hoog Jeremy J Primeau Tina T Myers Nancy N Vickery Tammi L TL Sturmoski Mark M Hagemann Ian S IS Miller Chris A CA Ellis Matthew J MJ Mardis Elaine R ER Hansen Ted T Fleming Timothy P TP Goedegebuure S Peter SP Gillanders William E WE

Cancer immunology research 20170615 7

Next-generation sequencing technologies have provided insights into the biology and mutational landscape of cancer. Here, we evaluate the relevance of cancer neoantigens in human breast cancers. Using patient-derived xenografts from three patients with advanced breast cancer (xenografts were designated as WHIM30, WHIM35, and WHIM37), we sequenced exomes of tumor and patient-matched normal cells. We identified 2,091 (WHIM30), 354 (WHIM35), and 235 (WHIM37) nonsynonymous somatic mutations. A compu ...[more]

PMID: 28619968

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Project description:ObjectiveTo develop a neoantigen-targeted personalized cancer treatment for non-small cell lung cancer (NSCLC), neoantigens were obtained from collected human lung cancer samples, and the utility of neoantigen and neoantigen-reactive T cells (NRTs) was assessed.MethodsTumor specimens from three patients with NSCLC were obtained and analyzed by whole-exome sequencing, and neoantigens were predicted accordingly. Dendritic cells and T lymphocytes were isolated, NRTs were elicited and IFN-γ ELISPOT tests were conducted. HLA-A2.1/Kb transgenic mice were immunized with peptides from HLA-A*02:01+patient with high immunogenicity, and NRTs were subjected to IFN-γ, IL-2 and TNF-α ELISPOT as well as time-resolved fluorescence assay for cytotoxicity assays to verify the immunogenicity in vitro. The HLA-A*02:01+lung cancer cell line was transfected with minigene and inoculated into the flanks of C57BL/6nu/nu mice and the NRTs induced by the immunogenic polypeptides from autologous HLA-A2.1/Kb transgenic mice were adoptively transfused to verify their immunogenicity in vivo.ResultsMultiple putative mutation-associated neoantigens with strong affinity for HLA were selected from each patient. Immunogenic neoantigen were identified in all three NSCLC patients, the potency of ACAD8-T105I, BCAR1-G23V and PLCG1-M425L as effective neoantigen to active T cells in suppressing tumor growth was further proven both in vitro and in vivo using HLA-A2.1/Kb transgenic mice and tumor-bearing mouse models.ConclusionNeoantigens with strong immunogenicity can be screened from NSCLC patients through the whole-exome sequencing of patient specimens and machine-learning-based neoantigen predictions. NRTs shown efficient antitumor responses in transgenic mice and tumor-bearing mouse models. Our results indicate that the development of neoantigen-based personalized immunotherapies in NSCLC is possible.PrecisNeoantigens with strong immunogenicity were screened from NSCLC patients. This research provides evidence suggesting that neoantigen-based therapy might serve as feasible treatment for NSCLC.

Dataset Information

Breast Cancer Neoantigens Can Induce CD8+ T-Cell Responses and Antitumor Immunity.

Publications

Breast Cancer Neoantigens Can Induce CD8<sup>+</sup> T-Cell Responses and Antitumor Immunity.

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