HLA Class I analysis provides insight into the genetic and epigenetic background of immune evasion in colorectal cancer with high microsatellite instability
HLA I类分子分析提供了高微卫星不稳定性大肠癌免疫逃逸的遗传和表观遗传背景
10.1053/j.gastro.2021.10.010
2021-10-20, Article
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BACKGROUND AND 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 (MSI-H CRCs) 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 (50%) tumors and loss of 61 alleles in 21 (18%) tumors. Based on the integrated analysis that enabled the immunological subclassification of MSI-H CRCs, 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 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.
First Authors:
Masahito Kawazu
Correspondence Authors:
Masahito Kawazu
All Authors:
Masahito Kawazu,Toshihide Ueno,Koichi Saeki,Nicolas Sax,Yosuke Togashi,Takayuki Kaneseki,Keigo Chida,Fumishi Kishigami,Kazuhito Sato,Shinya Kojima,Masafumi Otsuka,Akihito Kawazoe,Hitomi Nishinakamura,Yuka Maeda,Yoko Yamamoto,Kazuo Yamashita,Satoshi Inoue,Tokiyoshi Tanegashima,Daisuke Matsubara,Kenta Tane,Yosuke Tanaka,Hisae Iinuma,Yojiro Hashiguchi,Shoichi Hazama,Seik-Soon Khor,Katsushi Tokunaga,Masahiro Tsuboi,Toshiro Niki,Masatoshi Eto,Kohei Shitara,Toshihiko Torigoe,Soichiro Ishihara,Hiroyuki Aburatani,Hiroshi Haeno,Hiroyoshi Nishikawa,Hiroyuki Mano
