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解读体内免疫肽组揭示新的肿瘤抗原
2022-06-19 11:50
来源：小柯机器人

美国麻省理工学院Tyler Jacks研究团队通过解读体内免疫肽组揭示新的肿瘤抗原。2022年6月15日，《自然》杂志在线发表了这项成果。

研究人员表示，癌症的免疫监测需要主要组织相容性复合体I类（MHC-I）分子上多肽抗原的呈递。目前对MHC-I相关肽（统称为免疫肽组）进行分析的方法仅限于体外调查或大量的肿瘤裂解物，这限制了人们对体内癌症特异性抗原呈现模式的理解。
 
为了克服这些限制，研究人员在小鼠MHC-I基因（H2-K1）中设计了一个诱导性亲和标签，并将这个等位基因定位于KrasLSL-G12D/+Trp53fl/fl小鼠模型（KP/KbStrep）。 这种方法使研究人员能够从自体胰腺导管腺癌和体内的肺腺癌（LUAD）中精确分离MHC-I肽。此外，研究人员对LUAD的免疫肽组进行了分析，从肺泡2型细胞的起源一直到疾病晚期。在LUAD中，不同的肽呈现是无法通过mRNA表达或翻译效率预测的，可能是由翻译后机制驱动的。在体内用LUAD呈现的肽进行疫苗接种，可诱导正常小鼠和肿瘤小鼠的CD8+T细胞反应。
 
许多对LUAD有特异性的肽，包括免疫原性的肽，都表现出同源mRNA的最小表达，这促使研究人员重新考虑根据转录物丰度对肽进行分类的抗原预测管道。除了癌症，KbStrep等位基因与其他Cre驱动系兼容，从而可以探索体内的抗原表达，追求对基础免疫学、传染病和自身免疫的理解。
 
附：英文原文
 
Title: Deciphering the immunopeptidome in vivo reveals new tumour antigens

Author: Jaeger, Alex M., Stopfer, Lauren E., Ahn, Ryuhjin, Sanders, Emma A., Sandel, Demi A., Freed-Pastor, William A., Rideout, William M., Naranjo, Santiago, Fessenden, Tim, Nguyen, Kim B., Winter, Peter S., Kohn, Ryan E., Westcott, Peter M. K., Schenkel, Jason M., Shanahan, Sean-Luc, Shalek, Alex K., Spranger, Stefani, White, Forest M., Jacks, Tyler

Issue&Volume: 2022-06-15

Abstract: Immunosurveillance of cancer requires the presentation of peptide antigens on major histocompatibility complex classI (MHC-I) molecules1,2,3,4,5. Current approaches to profiling of MHC-I-associated peptides, collectively known as the immunopeptidome, are limited to in vitro investigation or bulk tumour lysates, which limits our understanding of cancer-specific patterns of antigen presentation in vivo6. To overcome these limitations, we engineered an inducible affinity tag into the mouse MHC-I gene (H2-K1) and targeted this allele to the KrasLSL-G12D/+Trp53fl/fl mouse model (KP/KbStrep)7. This approach enabled us to precisely isolate MHC-I peptides from autochthonous pancreatic ductal adenocarcinoma and from lung adenocarcinoma (LUAD) in vivo. In addition, we profiled the LUAD immunopeptidome from the alveolar type2 cell of origin up to late-stage disease. Differential peptide presentation in LUAD was not predictable by mRNA expression or translation efficiency and is probably driven by post-translational mechanisms. Vaccination with peptides presented by LUAD in vivo induced CD8+ Tcell responses in naive mice and tumour-bearing mice. Many peptides specific to LUAD, including immunogenic peptides, exhibited minimal expression of the cognate mRNA, which prompts the reconsideration of antigen prediction pipelines that triage peptides according to transcript abundance8. Beyond cancer, the KbStrep allele is compatible with other Cre-driver lines to explore antigen presentation in vivo in the pursuit of understanding basic immunology, infectious disease and autoimmunity.

DOI: 10.1038/s41586-022-04839-2

Source: https://www.nature.com/articles/s41586-022-04839-2

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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