Masahito Kawazu1, Toshihide Ueno2, Koichi Saeki3, Nicolas Sax4, Yosuke Togashi5, Takayuki Kanaseki6, Keigo Chida7, Fumishi Kishigami8, Kazuhito Sato9, Shinya Kojima2, Masafumi Otsuka2, Akihito Kawazoe10, Hitomi Nishinakamura5, Maeda Yuka5, Yoko Yamamoto9, Kazuo Yamashita4, Satoshi Inoue2, Tokiyoshi Tanegashima11, Daisuke Matsubara12, Kenta Tane13, Yosuke Tanaka2, Hisae Iinuma14, Yojiro Hashiguchi14, Shoichi Hazama15, Seik-Soon Khor16, Katsushi Tokunaga16, Masahiro Tsuboi17, Toshiro Niki12, Masatoshi Eto18, Kohei Shitara7, Toshihiko Torigoe6, Soichiro Ishihara9, Hiroyuki Aburatani19, Hiroshi Haeno3, Hiroyoshi Nishikawa20, Hiroyuki Mano21. 1. Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan. Electronic address: mkawz-tky@umin.ac.jp. 2. Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan. 3. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan. 4. KOTAI Biotechnologies, Inc, Osaka Japan. 5. Division of Cancer Immunology, Research Institute, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan. 6. Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan. 7. Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan. 8. Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan; Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan. 9. Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan. 10. Division of Cancer Immunology, Research Institute, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan; Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan. 11. Division of Cancer Immunology, Research Institute, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan; Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 12. Division of Integrative Pathology, Jichi Medical University, Shimotsukeshi, Japan. 13. Division of Cancer Immunology, Research Institute, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan; Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan. 14. Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan. 15. Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan. 16. Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 17. Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan. 18. Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 19. Genome Science Division, Research Center for Advanced Science and Technologies, The University of Tokyo, Tokyo, Japan. 20. Division of Cancer Immunology, Research Institute, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan; Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 21. Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan; Research Institute, National Cancer Center Research Institute, Tokyo, Japan.
Abstract
BACKGROUND & AIMS: A detailed understanding of antitumor immunity is essential for optimal cancer immune therapy. Although defective mutations in the B2M and HLA-ABC genes, which encode molecules essential for antigen presentation, have been reported in several studies, the effects of these defects on tumor immunity have not been quantitatively evaluated. METHODS: Mutations in HLA-ABC genes were analyzed in 114 microsatellite instability-high colorectal cancers using a long-read sequencer. The data were further analyzed in combination with whole-exome sequencing, transcriptome sequencing, DNA methylation array, and immunohistochemistry data. RESULTS: We detected 101 truncating mutations in 57 tumors (50%) and loss of 61 alleles in 21 tumors (18%). Based on the integrated analysis that enabled the immunologic subclassification of microsatellite instability-high colorectal cancers, we identified a subtype of tumors in which lymphocyte infiltration was reduced, partly due to reduced expression of HLA-ABC genes in the absence of apparent genetic alterations. Survival time of patients with such tumors was shorter than in patients with other tumor types. Paradoxically, tumor mutation burden was highest in the subtype, suggesting that the immunogenic effect of accumulating mutations was counterbalanced by mutations that weakened immunoreactivity. Various genetic and epigenetic alterations, including frameshift mutations in RFX5 and promoter methylation of PSMB8 and HLA-A, converged on reduced expression of HLA-ABC genes. CONCLUSIONS: Our detailed immunogenomic analysis provides information that will facilitate the improvement and development of cancer immunotherapy.
BACKGROUND & AIMS: A detailed understanding of antitumor immunity is essential for optimal cancer immune therapy. Although defective mutations in the B2M and HLA-ABC genes, which encode molecules essential for antigen presentation, have been reported in several studies, the effects of these defects on tumor immunity have not been quantitatively evaluated. METHODS: Mutations in HLA-ABC genes were analyzed in 114 microsatellite instability-high colorectal cancers using a long-read sequencer. The data were further analyzed in combination with whole-exome sequencing, transcriptome sequencing, DNA methylation array, and immunohistochemistry data. RESULTS: We detected 101 truncating mutations in 57 tumors (50%) and loss of 61 alleles in 21 tumors (18%). Based on the integrated analysis that enabled the immunologic subclassification of microsatellite instability-high colorectal cancers, we identified a subtype of tumors in which lymphocyte infiltration was reduced, partly due to reduced expression of HLA-ABC genes in the absence of apparent genetic alterations. Survival time of patients with such tumors was shorter than in patients with other tumor types. Paradoxically, tumor mutation burden was highest in the subtype, suggesting that the immunogenic effect of accumulating mutations was counterbalanced by mutations that weakened immunoreactivity. Various genetic and epigenetic alterations, including frameshift mutations in RFX5 and promoter methylation of PSMB8 and HLA-A, converged on reduced expression of HLA-ABC genes. CONCLUSIONS: Our detailed immunogenomic analysis provides information that will facilitate the improvement and development of cancer immunotherapy.