套细胞淋巴瘤:neoantigen主要来自Ig可变区基因突变
  • 肿瘤体细胞突变可产生新抗原,每位患者的新抗原的鉴定和验证是目前的难点;
  • 采用整合基因组和蛋白质组方法,分析组织相容性复合体(MHC)I和II分子提呈的肿瘤抗原肽,可发现新抗原;
  • 在套细胞淋巴瘤中,新抗原主要来自于免疫球蛋白(Ig)可变区的体细胞突变,被MHC II特异性地提呈;
  • 新抗原特异性循环CD4(+)T细胞,可介导对淋巴瘤细胞的杀伤;
  • Ig可变区体细胞突变产生的新抗原,可作为淋巴瘤免疫治疗的新靶点。
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Nature [IF:42.778]

Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens

抗原提呈分析揭示淋巴瘤免疫球蛋白新抗原的识别

10.1038/nature21433

2017-03-30, Letter

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Cancer somatic mutations can generate neoantigens that distinguish malignant from normal cells. However, the personalized identification and validation of neoantigens remains a major challenge. Here we discover neoantigens in human mantle-cell lymphomas by using an integrated genomic and proteomic strategy that interrogates tumour antigen peptides presented by major histocompatibility complex (MHC) class I and class II molecules. We applied this approach to systematically characterize MHC ligands from 17 patients. Remarkably, all discovered neoantigenic peptides were exclusively derived from the lymphoma immunoglobulin heavy- or light-chain variable regions. Although we identified MHC presentation of private polymorphic germline alleles, no mutated peptides were recovered from non-immunoglobulin somatically mutated genes. Somatic mutations within the immunoglobulin variable region were almost exclusively presented by MHC class II. We isolated circulating CD4(+) T cells specific for immunoglobulin-derived neoantigens and found these cells could mediate killing of autologous lymphoma cells. These results demonstrate that an integrative approach combining MHC isolation, peptide identification, and exome sequencing is an effective platform to uncover tumour neoantigens. Application of this strategy to human lymphoma implicates immunoglobulin neoantigens as targets for lymphoma immunotherapy.

First Authors:
Michael S Khodadoust,Niclas Olsson

Correspondence Authors:
Joshua E Elias,Ash A Alizadeh

All Authors:
Michael S Khodadoust,Niclas Olsson,Lisa E Wagar,Ole A W Haabeth,Binbin Chen,Kavya Swaminathan,Keith Rawson,Chih Long Liu,David Steiner,Peder Lund,Samhita Rao,Lichao Zhang,Caleb Marceau,Henning Stehr,Aaron M Newman,Debra K Czerwinski,Victoria E H Carlton,Martin Moorhead,Malek Faham,Holbrook E Kohrt,Jan Carette,Michael R Green,Mark M Davis,Ronald Levy,Joshua E Elias,Ash A Alizadeh

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