HLA Class I Analysis Provides Insight Into the Genetic and Epigenetic Background of Immune Evasion in Colorectal Cancer With High Microsatellite Instability

Masahito Kawazu, Toshihide Ueno, Koichi Saeki, Nicolas Sax, Yosuke Togashi, Takayuki Kanaseki, Keigo Chida, Fumishi Kishigami, Kazuhito Sato, Shinya Kojima, Masafumi Otsuka, Akihito Kawazoe, Hitomi Nishinakamura, Maeda Yuka, Yoko Yamamoto, Kazuo Yamashita, Satoshi Inoue, Tokiyoshi Tanegashima, Daisuke Matsubara, Kenta TaneYosuke 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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)799-812
Number of pages14
JournalGastroenterology
Volume162
Issue number3
DOIs
Publication statusPublished - Mar 2022
Externally publishedYes

Keywords

  • Antitumor Immunity
  • Class I Major Histocompatibility Complex
  • Long-Read Sequencer
  • Microsatellite Instability–High Colorectal Cancer

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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