Abstract 5721: Neoantigen load and HLA-class I expression characterize a subset of HR-proficient high-grade serous ovarian carcinomas with favorable prognosis and T cell-inflamed phenotype
Authors: Hirokazu Matsushita, Kosei Hasegawa, Katsutoshi Oda, Shogo Yamamoto, Kayo Asada, Akira Yabuno, Akira Nishijima, Takahiro Karasaki, Yuji Ikeda, Keiichi Fujiwara, Hiroyuki Aburatani, Kakimi Kazuhiro
Journal: Cancer Research (2018)

Abstract Aim: Around 50% of high-grade serous ovarian carcinomas (HGSC) have deficiency in homologous recombination (HR) pathways. There has been increased evidence of benefit for the use of poly ADP ribose polymerase (PARP) inhibitors in a group of HGSC patients who especially have HR-deficient tumors. Therefore, it is needed to develop a new treatment strategy for the rest, an HR-proficient tumor. The aim of this study is to investigate immunological background of HR-proficient HGSC by integrated molecular analysis to explore the subset that would become candidates for immunotherapy such as immune checkpoint inhibitors. Methods: In total, 80 cases of HGSC were analyzed in this study. Exome and RNA sequencing were performed to identify germline and somatic mutations. Methylation arrays were also carried out to evaluate BRCA1 and RAD51C promoter methylation status. Predicted neoantigens derived from mutations were identified based on the MHC class I binding prediction algorithm NetMHCpan 2.8. Immune profile in the tumor was assessed by differential gene expression analysis and gene set enrichment analysis (GSEA) using RNA sequencing data. Neoantigen load, antigen presentation, immune profile and their relevance to clinical outcomes were also investigated. Results: Either BRCA1/2, RAD51C/D mutations, or BRCA1, RAD51C promoter methylation was defined as HR-deficient. A total of 34 (42.5%) and 46 (57.5%) patients were classified as having HR-deficient and HR-proficient tumors, respectively. As expected, the numbers of predicted neoantigens were lower in HR-proficient than HR-deficient tumors (p&amp;lt;0.01). However, 40% of the patients with HR-proficient tumors still had high numbers of neoantigens and displayed better survival trend than those who had lower numbers of neoantigens. Incorporation of HLA-class I expression status in the analysis revealed that the patients who had both high neoantigen number and high HLA-class I expression showed improved survival in HR-proficient HGSC (p=0.02). GSEA demonstrated that the gene sets for effector memory CD8, TH1, and type I and type II interferon (IFN) responses were enriched in those patients. Conclusions: The number of neoantigens and HLA-class I expression characterized a subset of HR-proficient HGSC with improved prognosis and immunologically hot phenotype. This subset might be a candidate target for immune checkpoint inhibitors rather than PARP inhibitors. Citation Format: Hirokazu Matsushita, Kosei Hasegawa, Katsutoshi Oda, Shogo Yamamoto, Kayo Asada, Akira Yabuno, Akira Nishijima, Takahiro Karasaki, Yuji Ikeda, Keiichi Fujiwara, Hiroyuki Aburatani, Kakimi Kazuhiro. Neoantigen load and HLA-class I expression characterize a subset of HR-proficient high-grade serous ovarian carcinomas with favorable prognosis and T cell-inflamed phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5721.