高微卫星不稳性大肠癌免疫逃逸或与HLA I类分子突变相关
创作:Lexi 审核:Lexi 2021年11月08日
  • 在57例(50%)微卫星不稳性高的结直肠癌样本中检测到HLA-ABC基因的101个截断突变,在21例(18%)样本中检测到61个等位基因缺失;
  • 发现一种淋巴细胞浸润减少的肿瘤亚型,部分原因是HLA-ABC基因表达减少,但无明显遗传改变;
  • 该类患者生存期短于其他类患者,但肿瘤突变负荷最高,提示累积突变的免疫原性作用被减弱的免疫反应性突变抵消;
  • 各种(表观)遗传改变,包括RFX5移位突变和PSMB8启动子甲基化,都集中于HLA-ABC基因的表达减少。
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Lexi
详细了解抗肿瘤免疫是最佳肿瘤免疫治疗的必要条件。B2M和HLA-ABC基因编码抗原呈递所必需的分子,这些基因的缺陷突变对肿瘤免疫的影响尚未得到定量评价。最新发表在Gastroenterology的研究,利用长读测序仪分析114例微卫星不稳性高的结直肠癌(MSI-H CRC)中HLA-ABC基因突变,并结合全外显子组测序、转录组测序、DNA甲基化阵列和免疫组化数据进一步分析,提供了有助于改进和发展癌症免疫治疗的信息。
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Gastroenterology [IF:22.682]

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

Abstract & Authors:展开

Abstract:收起
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

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