Protein citrullination as a source of cancer neoantigens.
Protein citrullination as a source of cancer neoantigens.
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DOI：
10.1136/jitc-2021-002549
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发表时间：
2021-06
影响因子：
10.9
通讯作者：
Hanash S
中科院分区：
文献类型：
--
作者：
Katayama H;Kobayashi M;Irajizad E;Sevillarno A;Patel N;Mao X;Rusling L;Vykoukal J;Cai Y;Hsiao F;Yu CY;Long J;Liu J;Esteva F;Fahrmann J;Hanash S
瓜氨酸对蛋白质的翻译后修饰是由蛋白质精氨酸脱亚胺酶(PADI)家族成员介导的，与自身免疫性疾病有关。PADI-瓜氨酸体在癌症免疫反应中的作用尚未得到评估。我们假设PADI介导的瓜氨酸体是癌症中诱导免疫反应的新抗原的来源。采用蛋白质组学方法对196个癌细胞系中PADI家族成员的蛋白质表达进行了研究。使用来自癌症基因组图谱的信使RNA数据集评估基因表达。对乳腺癌组织切片进行PADI2和多肽-瓜氨酸的免疫组织化学分析。为了研究蛋白质瓜氨酸化与抗原提呈的关系，我们在乳腺癌细胞系中分析了推测的主要组织相容性复合体-II(MHC-II)结合范围内的12-34位瓜氨酸多肽。我们进一步用质谱仪对156名乳腺癌患者和113名无癌对照的免疫球蛋白结合瓜氨酸组进行了评估。蛋白质组和基因表达分析显示，PADI2在包括乳腺癌在内的几种癌症中都有高表达。免疫组织化学分析显示，PADI2在ER−肿瘤组织中表达增加(P<；0.0001)，PADI2蛋白表达与多肽-瓜氨酸染色呈正相关(P<；0.0001)。PADI2的表达与B细胞免疫特征和MHC-II结合的瓜氨酸多肽呈显著正相关。与对照组相比，新诊断的乳腺癌患者循环中的瓜氨酸抗原抗体复合体增多(p=0.0012)。与瓜氨酸体相关的免疫反应是乳腺癌新抗原的丰富来源，具有诊断和治疗应用的潜力。
Citrulline post-translational modification of proteins is mediated by protein arginine deiminase (PADI) family members and has been associated with autoimmune diseases. The role of PADI-citrullinome in immune response in cancer has not been evaluated. We hypothesized that PADI-mediated citrullinome is a source of neoantigens in cancer that induces immune response. Protein expression of PADI family members was evaluated in 196 cancer cell lines by means of indepth proteomic profiling. Gene expression was assessed using messenger RNA data sets from The Cancer Genome Atlas. Immunohistochemical analysis of PADI2 and peptidyl-citrulline was performed using breast cancer tissue sections. Citrullinated 12–34-mer peptides in the putative Major Histocompatibility Complex-II (MHC-II) binding range were profiled in breast cancer cell lines to investigate the relationship between protein citrullination and antigen presentation. We further evaluated immunoglobulin-bound citrullinome by mass spectrometry using 156 patients with breast cancer and 113 cancer-free controls. Proteomic and gene expression analyses revealed PADI2 to be highly expressed in several cancer types including breast cancer. Immunohistochemical analysis of 422 breast tumor tissues revealed increased expression of PADI2 in ER− tumors (p<0.0001); PADI2 protein expression was positively correlated (p<0.0001) with peptidyl-citrulline staining. PADI2 expression exhibited strong positive correlations with a B cell immune signature and with MHC-II-bound citrullinated peptides. Increased circulating citrullinated antigen–antibody complexes occurred among newly diagnosed breast cancer cases relative to controls (p=0.0012). An immune response associated with citrullinome is a rich source of neoantigens in breast cancer with a potential for diagnostic and therapeutic applications.
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影响因子：
11.2
作者：
Ladd JJ;Chao T;Johnson MM;Qiu J;Chin A;Israel R;Pitteri SJ;Mao J;Wu M;Amon LM;McIntosh M;Li C;Prentice R;Disis N;Hanash S
通讯作者：
Hanash S
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
16.6
作者：
Chen F;Zhang Y;Bossé D;Lalani AA;Hakimi AA;Hsieh JJ;Choueiri TK;Gibbons DL;Ittmann M;Creighton CJ
通讯作者：
Creighton CJ
影响因子：
11.2
作者：
Faça VM;Hanash SM
通讯作者：
Hanash SM
影响因子：
82.9
作者：
Binnewies M;Roberts EW;Kersten K;Chan V;Fearon DF;Merad M;Coussens LM;Gabrilovich DI;Ostrand-Rosenberg S;Hedrick CC;Vonderheide RH;Pittet MJ;Jain RK;Zou W;Howcroft TK;Woodhouse EC;Weinberg RA;Krummel MF
通讯作者：
Krummel MF