研究揭示微卫星不稳定肿瘤中的多表位移码突变
2020-12-03   阅读:464   来源:细胞

美国西奈山医院伊坎医学院Nina Bhardwaj小组揭示微卫星不稳定肿瘤中的共享免疫原性多表位移码突变。这一研究成果于2020年11月30日在线发表在国际学术期刊《细胞》上。

研究人员确定了编码多个表位的肿瘤特异性移码,这些表位源自高度微卫星不稳定性(MSI-H)子宫内膜癌、结直肠癌和胃癌患者之间共有的插入缺失突变。从这些共有的移码中衍生出的抗原决定簇具有较高的群体发生率,在许多肿瘤亚克隆中的广泛存在,并且预计将与MSI-H患者队列中最常见的MHC等位基因结合。

由这些突变产生的新抗原与自身和病毒抗原明显不同,这标志着可能具有高度免疫原性的新型肿瘤抗原。研究人员还使用从健康供体和MSI-H癌症患者中分离的血液单核细胞在T细胞刺激实验中进一步证实了移码肽的免疫原性。这些研究发现了MSI-H癌症和Lynch综合征患者中由共享移码突变所产生的肿瘤特异性抗原具有的广泛存在和强免疫原性,可用于设计常见的“现成”癌症疫苗。

据悉,MSI-H肿瘤的特征是高肿瘤突变负担和对检查站封锁的反应能力。

附:英文原文

Title: Shared Immunogenic Poly-Epitope Frameshift Mutations in Microsatellite Unstable Tumors

Author: Vladimir Roudko, Cansu Cimen Bozkus, Theofano Orfanelli, Christopher B. McClain, Caitlin Carr, Timothy O’Donnell, Lauren Chakraborty, Robert Samstein, Kuan-lin Huang, Stephanie V. Blank, Benjamin Greenbaum, Nina Bhardwaj

Issue&Volume: 2020-11-30

Abstract: Microsatellite instability-high (MSI-H) tumors are characterized by high tumor mutationburden and responsiveness to checkpoint blockade. We identified tumor-specific frameshiftsencoding multiple epitopes that originated from indel mutations shared among patientswith MSI-H endometrial, colorectal, and stomach cancers. Epitopes derived from theseshared frameshifts have high population occurrence rates, wide presence in many tumorsubclones, and are predicted to bind to the most frequent MHC alleles in MSI-H patientcohorts. Neoantigens arising from these mutations are distinctly unlike self and viralantigens, signifying novel groups of potentially highly immunogenic tumor antigens.We further confirmed the immunogenicity of frameshift peptides in T cell stimulationexperiments using blood mononuclear cells isolated from both healthy donors and MSI-Hcancer patients. Our study uncovers the widespread occurrence and strong immunogenicityof tumor-specific antigens derived from shared frameshift mutations in MSI-H cancerand Lynch syndrome patients, suitable for the design of common “off-the-shelf” cancervaccines.

DOI: 10.1016/j.cell.2020.11.004

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