An Integrated Genomic, Proteomic, and Immunopeptidomic Approach to Discover Treatment-Induced Neoantigens.
An Integrated Genomic, Proteomic, and Immunopeptidomic Approach to Discover Treatment-Induced Neoantigens.
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DOI：
10.3389/fimmu.2021.662443
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发表时间：
2021
影响因子：
7.3
通讯作者：
Elias JE
中科院分区：
文献类型：
--
作者：
Olsson N;Heberling ML;Zhang L;Jhunjhunwala S;Phung QT;Lin S;Anania VG;Lill JR;Elias JE
所有有核哺乳动物细胞都表达主要组织相容性复合体 (MHC) 蛋白，这些蛋白在细胞表面呈现肽以进行免疫监视。这些 MHC 呈递肽 (pMHC) 对于指导 T 细胞针对含有源自病原体或体细胞突变的非自身抗原的细胞做出反应是必需的。肿瘤特异性抗原库的改变——特别是携带突变的肽（新抗原）的新型 MHC 呈现——可以成为抗肿瘤免疫反应的有效目标。在这里，我们采用了集成的基因组和蛋白质组抗原发现策略，旨在使用人类淋巴瘤细胞系 GRANTA-519 测量干扰素 γ (IFN-γ) 如何改变抗原呈递。 IFN-γ 处理导致 126 种差异表达的蛋白质（占所有定量蛋白质的 2%），其中包括抗原呈递机制和干扰素信号传导途径的组成部分，以及 MHC 分子本身。此外，还发现几个蛋白酶体亚基受到调节，这与之前通过 IFN-γ 暴露诱导免疫蛋白酶体的报道一致。这一发现表明，对 IFN-γ 的适度蛋白质组反应可能会对细胞的抗原/表位库产生更大的改变。因此，MHC 免疫沉淀和洗脱肽库的质谱分析揭示了 IFN-γ 诱导的独特特征，其中 951 个独特的肽由 MHC-I 重复呈现，582 个独特的肽由 MHC-II 重复呈现。此外，另一组 pMHC 包括几种候选新抗原，通过改变的相对丰度区分对照和 IFN-γ 样品。因此，我们开发了一个分类系统来区分由于抗原加工变化导致的新肽表达改变而差异呈现的肽。总而言之，这些数据表明 IFN-γ 可以通过身份和丰度重塑抗原库。将这种方法扩展到具有更大临床相关性的模型可能有助于制定策略，通过这些策略有意重塑免疫肽库，以改善内源性或疫苗诱导的抗肿瘤免疫反应和潜在的抗病毒免疫反应。
All nucleated mammalian cells express major histocompatibility complex (MHC) proteins that present peptides on cell surfaces for immune surveillance. These MHC-presented peptides (pMHC) are necessary for directing T-cell responses against cells harboring non-self antigens derived from pathogens or from somatic mutations. Alterations in tumor-specific antigen repertoires — particularly novel MHC presentation of mutation-bearing peptides (neoantigens) — can be potent targets of anti-tumor immune responses. Here we employed an integrated genomic and proteomic antigen discovery strategy aimed at measuring how interferon gamma (IFN-γ) alters antigen presentation, using a human lymphoma cell line, GRANTA-519. IFN-γ treatment resulted in 126 differentially expressed proteins (2% of all quantified proteins), which included components of antigen presentation machinery and interferon signaling pathways, and MHC molecules themselves. In addition, several proteasome subunits were found to be modulated, consistent with previous reports of immunoproteasome induction by IFN-γ exposure. This finding suggests that a modest proteomic response to IFN-γ could create larger alteration to cells’ antigen/epitope repertoires. Accordingly, MHC immunoprecipitation followed by mass spectrometric analysis of eluted peptide repertoires revealed exclusive signatures of IFN-γ induction, with 951 unique peptides reproducibly presented by MHC-I and 582 presented by MHC-II. Furthermore, an additional set of pMHCs including several candidate neoantigens, distinguished control and the IFN-γ samples by their altered relative abundances. Accordingly, we developed a classification system to distinguish peptides which are differentially presented due to altered expression from novel peptides resulting from changes in antigen processing. Taken together, these data demonstrate that IFN-γ can re-shape antigen repertoires by identity and by abundance. Extending this approach to models with greater clinical relevance could help develop strategies by which immunopeptide repertoires are intentionally reshaped to improve endogenous or vaccine-induced anti-tumor immune responses and potentially anti-viral immune responses.
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影响因子：
3.3
作者：
Hamanishi J;Mandai M;Matsumura N;Abiko K;Baba T;Konishi I
通讯作者：
Konishi I
影响因子：
32.4
作者：
Abelin JG;Keskin DB;Sarkizova S;Hartigan CR;Zhang W;Sidney J;Stevens J;Lane W;Zhang GL;Eisenhaure TM;Clauser KR;Hacohen N;Rooney MS;Carr SA;Wu CJ
通讯作者：
Wu CJ
影响因子：
56.9
作者：
HUNT, DF;MICHEL, H;SETTE, A
通讯作者：
SETTE, A
影响因子：
11.4
作者：
BURRONE, OR;KEFFORD, RF;MILSTEIN, C
通讯作者：
MILSTEIN, C
影响因子：
4.6
作者：
Chen H;Li L;Weimershaus M;Evnouchidou I;van Endert P;Bouvier M
通讯作者：
Bouvier M