HLA-A24 ligandome analysis of colon and lung cancer cells identifies a novel cancer-testis antigen and a neoantigen that elicits specific and strong CTL responses

• Published in: Oncoimmunology Vol. 6; no. 4; p. e1293214
• Main Authors: Kochin, Vitaly, Kanaseki, Takayuki, Tokita, Serina, Miyamoto, Sho, Shionoya, Yosuke, Kikuchi, Yasuhiro, Morooka, Daichi, Hirohashi, Yoshihiko, Tsukahara, Tomohide, Watanabe, Kazue, Toji, Shingo, Kokai, Yasuo, Sato, Noriyuki, Torigoe, Toshihiko
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 03.04.2017; Taylor & Francis Group
• Subjects: Cancer immunotherapy; CTL; HLA ligandome; neoantigen; Original Research; tumor-associated antigen; neoantigen; HLA ligandome; CTL; tumor-associated antigen; Cancer immunotherapy
• ISSN: 2162-402X; 2162-4011; 2162-402X
• DOI: 10.1080/2162402X.2017.1293214

This study focused on HLA-A24 and comprehensively analyzed the ligandome of colon and lung cancer cells without the use of MHC-binding in silico prediction algorithms. Affinity purification using the antibody specific to HLA-A24 followed by LC-MS/MS sequencing was used to detect peptides, which harbored the known characteristics of HLA-A24 peptides in terms of length and anchor motifs. Ligandome analysis demonstrated the natural presentation of two different types of novel tumor-associated antigens. The ligandome contained a peptide derived from SUV39H2, a gene found to be expressed in a variety of cancers but not in normal tissues (except for the testis). The SUV39H2 peptide is immunogenic and elicits cytotoxic CD8 + T-cell (CTL) responses against cancer cells and is thus a novel cancer-testis antigen. Moreover, we found that microsatellite instability (MSI)-colon cancer cells displayed a neoepitope with an amino-acid substitution, while microsatellite stable (MSS)-colon and lung cancer cells displayed its counterpart peptide without the substitution. Structure modeling of peptide-HLA-A24 complexes predicted that the mutated residue at P8 was accessible to T-cell receptors. The neoepitope readily elicited CTL responses, which discriminated it from its wild-type counterpart, and the CTLs exhibited considerably high cytotoxicity against MSS-colon cancer cells carrying the responsible gene mutation. The specific and strong CTL lysis observed in this study fosters our understanding of immune surveillance against neoantigens.