Identification of a neoantigen epitope in a melanoma patient with good response to anti-PD-1 antibody therapy

Chizu Nonomura, Masaki Otsuka, Ryota Kondou, Akira Iizuka, Haruo Miyata, Tadashi Ashizawa, Naoki Sakura, Shusuke Yoshikawa, Yoshio Kiyohara, Keiichi Ohshima, Kenichi Urakami, Takeshi Nagashima, Sumiko Ohnami, Masatoshi Kusuhara, Koichi Mitsuya, Nakamasa Hayashi, Yoko Nakasu, Tohru Mochizuki, Ken Yamaguchi, Yasuto Akiyama
Immunology Letters 2019 March 14
Recent advances in next-generation sequencing have enabled rapid and efficient evaluation of the mutational landscape of cancers. As a result, many cancer-specific neoantigens, which can generate antitumor cytotoxic T-cells inside tumors, have been identified. Previously, we reported a metastatic melanoma case with high tumor mutation burden, who obtained complete remission after anti-PD-1 therapy and surgical resection. The rib metastatic lesion, which was used for whole-exome sequencing and gene expression profiling in the HOPE project, showed upregulated expression of PD-L1 mRNA and a high single-nucleotide variants number of 2,712. In the current study, we focused on a metastatic melanoma case and candidate epitopes among nonsynonymous mutant neoantigens of 1,348 variants were investigated using a peptide-HLA binding algorithm, in vitro cytotoxic T-cell induction assay and HLA tetramer staining. Specifically, from mutant neoantigen data, a total of 21,066 9-mer mutant epitope candidates including a mutated amino acid anywhere in the sequence were applied to the NetMHC binding prediction algorithm. From in silico data, we identified the top 26 mutant epitopes with strong-binding capacity. A cytotoxic T-cell induction assay using 5 cancer patient-derived PBMCs revealed that the mutant ARMT1 peptide sequence (FYGKTILWF) with HLA-A*2402 restriction was an efficient neoantigen, which was detected at a frequency of approximately 0.04% in the HLA-A24 tetramer stain. The present success in identifying a novel mutant antigen epitope might be applied to clinical neoantigen screening in the context of an NGS-equipped medical facility for the development of the next-generation neoantigen cancer vaccines.

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