期刊首页 优先出版 当期阅读 过刊浏览 作者中心 关于期刊 English

《工程(英文)》 >> 2023年 第22卷 第3期 doi: 10.1016/j.eng.2022.06.008

肿瘤特异性环状RNA来源抗原肽被证实存在于肝胆肿瘤中

a Fudan University Shanghai Cancer Center, Shanghai 200032, China
b Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China
c University of Chinese Academy of Sciences, Beijing 100049, China
d School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
e State Key Laboratory of Pharmaceutical Biotechnology & Model Animal Research Center of Nanjing University and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
f School of Medicine, Nanjing University, Nanjing 210093, China
g The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
h National Center for Liver Cancer, Shanghai 200441, China
i Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200433, China
j State Key Laboratory of Cell Biology & Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
k Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
l Faculty of Health Sciences, University of Macau, Macao 999078, China
m Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education & Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China

# These authors contributed equally to this work.

收稿日期: 2022-03-18 修回日期: 2022-05-21 录用日期: 2022-06-07 发布日期: 2022-07-20

下一篇 上一篇

摘要

由于缺乏经证实具备免疫原性的多肽,基于肿瘤抗原的免疫治疗应用受到限制。在本研究中,利用肝胆肿瘤类器官分析了环状RNA(circRNA)作为肿瘤抗原肽新来源的潜力。使用RNA测序(RNA-seq)和基于算法的评分工具,预测出27 个类器官中3950 个肿瘤特异性circRNA 可翻译18 971 条抗原肽。抗原图谱显示,11 个氨基酸长度(mer)的肽和人类白细胞抗原(HLA)-A结合肽的免疫原性相关评分最高。通过对5 个类器官进行基于质谱的免疫肽组学分析,直接证实其中三个类器官的13 条抗原肽为HLA-A、HLA-B 和HLA-C(HLA-ABC)结合肽。通过流式细胞仪和酶联免疫分析发现,HLA-ABC 呈递的cricRNA来源肿瘤特异性肽可以刺激CD8 T细胞,使其CD107a 和干扰素γ(IFNγ)共表达提高、IFNγ分泌增加。细胞杀伤实验证实,经circRNA 来源免疫原性肽活化的T 细胞可杀伤类器官细胞。值得注意的是,来自circTBC1D15 的抗原肽YGFNEILKK不仅可以被HLA-ABC呈递,还能活化T细胞,显著降低肿瘤类器官活率。本研究的发现提供了一种产生肿瘤抗原的重要来源,提示肿瘤特异性circRNA 可作为抗肿瘤靶点。

补充材料

图片

图1

图2

图3

图4

图5

图6

参考文献

[ 1 ] Hu Z, Ott PA, Wu CJ. Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nat Rev Immunol 2018;18(3):168‒82. 链接1

[ 2 ] Basu R, Whitlock BM, Husson J, Le Floc’h A, Jin W, Oyler-Yaniv A, et al. Cytotoxic T cells use mechanical force to potentiate target cell killing. Cell 2016;165(1):100‒10. 链接1

[ 3 ] Parkhurst MR, Robbins PF, Tran E, Prickett TD, Gartner JJ, Jia L, et al. Unique neoantigens arise from somatic mutations in patients with gastrointestinal cancers. Cancer Discov 2019;9(8):1022‒35. 链接1

[ 4 ] Cohen CJ, Gartner JJ, Horovitz-Fried M, Shamalov K, Trebska-McGowan K, Bliskovsky VV, et al. Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes. J Clin Invest 2015;125(10):3981‒91. 链接1

[ 5 ] Hansen UK, Ramskov S, Bjerregaard AM, Borch A, Andersen R, Draghi A, et al. Tumor-infiltrating T cells from clear cell renal cell carcinoma patients recognize neoepitopes derived from point and frameshift mutations. Front Immunol 2020;11:373. 链接1

[ 6 ] Yang W, Lee KW, Srivastava RM, Kuo F, Krishna C, Chowell D, et al. Immunogenic neoantigens derived from gene fusions stimulate T cell responses. Nat Med 2019;25(5):767‒75. 链接1

[ 7 ] Pamudurti NR, Bartok O, Jens M, Ashwal-Fluss R, Stottmeister C, Ruhe L, et al. Translation of circRNAs. Mol Cell 2017;66(1):9‒21.e7. 链接1

[ 8 ] Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L, Zhang Y, et al. The landscape of circular RNA in cancer. Cell 2019;176(4):869‒881.e13. 链接1

[ 9 ] Wang Y, Wang Z. Efficient backsplicing produces translatable circular mRNAs. RNA 2015;21(2):172‒9. 链接1

[10] Zhang M, Zhao K, Xu X, Yang Y, Yan S, Wei P, et al. A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. Nat Commun 2018;9(1):4475. 链接1

[11] Chen CY, Sarnow P. Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. Science 1995;268(5209):415‒7. 链接1

[12] Zhao J, Wu J, Xu T, Yang Q, He J, Song X. IRESfinder: identifying RNA internal ribosome entry site in eukaryotic cell using framed k-mer features. J Genet Genomics 2018;45(7):403‒6. 链接1

[13] Deniger DC, Pasetto A, Robbins PF, Gartner JJ, Prickett TD, Paria BC, et al. T-cell responses to TP53 “Hotspot” mutations and unique neoantigens expressed by human ovarian cancers. Clin Cancer Res 2018;24(22):5562‒73. 链接1

[14] Broutier L, Mastrogiovanni G, Verstegen MM, Francies HE, Gavarró LM, Bradshaw CR, et al. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nat Med 2017;23(12):1424‒35. 链接1

[15] Saito Y, Muramatsu T, Kanai Y, Ojima H, Sukeda A, Hiraoka N, et al. Establishment of patient-derived organoids and drug screening for biliary tract carcinoma. Cell Rep 2019;27(4):1265‒76.e4. 链接1

[16] Zumwalde NA, Haag JD, Sharma D, Mirrielees JA, Wilke LG, Gould MN, et al. Analysis of immune cells from human mammary ductal epithelial organoids reveals Vδ2+ T cells that efficiently target breast carcinoma cells in the presence of bisphosphonate. Cancer Prev Res 2016;9(4):305‒16. 链接1

[17] Rogoz A, Reis BS, Karssemeijer RA, Mucida D. A 3-D enteroid-based model to study T-cell and epithelial cell interaction. J Immunol Methods 2015;421:89‒95. 链接1

[18] Dijkstra KK, Cattaneo CM, Weeber F, Chalabi M, van de Haar J, Fanchi LF, et al. Generation of tumor-reactive T cells by co-culture of peripheral blood lymphocytes and tumor organoids. Cell 2018;174(6):1586‒98.e12. 链接1

[19] Jacob F, Salinas RD, Zhang DY, Nguyen PTT, Schnoll JG, Wong SZH, et al. A patient-derived glioblastoma organoid model and biobank recapitulates interand intra-tumoral heterogeneity. Cell 2020;180(1):188‒204.e22. 链接1

[20] Schnalzger TE, de Groot MH, Zhang C, Mosa MH, Michels BE, Röder J, et al. 3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids. EMBO J 2019;38(12):38. 链接1

[21] Villanueva A. Hepatocellular carcinoma. N Engl J Med 2019;380(15):1450‒62. 链接1

[22] Zhao Y, Li ZX, Zhu YJ, Fu J, Zhao XF, Zhang YN, et al. Single-cell transcriptome analysis uncovers intratumoral heterogeneity and underlying mechanisms for drug resistance in hepatobiliary tumor organoids. Adv Sci 2021;8(11):e2003897. 链接1

[23] Liu C, Yang X, Duffy B, Mohanakumar T, Mitra RD, Zody MC, et al. ATHLATES: accurate typing of human leukocyte antigen through exome sequencing. Nucleic Acids Res 2013;41(14):e142. 链接1

[24] Kawaguchi S, Higasa K, Shimizu M, Yamada R, Matsuda F. HLA-HD: an accurate HLA typing algorithm for next-generation sequencing data. Hum Mutat 2017;38(7):788‒97. 链接1

[25] Nariai N, Kojima K, Saito S, Mimori T, Sato Y, Kawai Y, et al. HLA-VBSeq: accurate HLA typing at full resolution from whole-genome sequencing data. BMC Genomics 2015;16(S2):S7. 链接1

[26] Zhang XO, Wang HB, Zhang Y, Lu X, Chen LL, Yang L. Complementary sequence-mediated exon circularization. Cell 2014;159(1):134‒47. 链接1

[27] Wei Z, Zhou C, Zhang Z, Guan M, Zhang C, Liu Z, et al. The landscape of tumor fusion neoantigens: a pan-cancer analysis. iScience 2019;21:249‒60. 链接1

[28] Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, et al. ClusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innovation 2021;2(3):100141. 链接1

[29] Wang X, Dong Y, Wu Z, Wang G, Shi Y, Zheng Y. Machine learning-based comparative analysis of pan-cancer and pan-normal tissues identifies pancancer tissue-enriched circRNAs related to cancer mutations as potential exosomal biomarkers. Front Oncol 2021;11:703461. 链接1

[30] Tian J, Fu Y, Li Q, Xu Y, Xi X, Zheng Y, et al. Differential expression and bioinformatics analysis of circRNA in PDGF-BB-induced vascular smooth muscle cells. Front Genet 2020;11:530. 链接1

[31] Li Z, Chen G, Cai Z, Dong X, He L, Qiu L, et al. Profiling of hepatocellular carcinoma neoantigens reveals immune microenvironment and clonal evolution related patterns. Chin J Cancer Res 2021;33(3):364‒78. 链接1

[32] Newey A, Griffiths B, Michaux J, Pak HS, Stevenson BJ, Woolston A, et al. Immunopeptidomics of colorectal cancer organoids reveals a sparse HLA class I neoantigen landscape and no increase in neoantigens with interferon or MEK-inhibitor treatment. J Immunother Cancer 2019;7(1):309. 链接1

[33] Lorenzo-Herrero S, Sordo-Bahamonde C, Gonzalez S, López-Soto A. CD107a degranulation assay to evaluate immune cell antitumor activity. Methods Mol Biol 2019;1884:119‒30.

[34] Sachs N, de Ligt J, Kopper O, Gogola E, Bounova G, Weeber F, et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell 2018;172(1‒2):373‒86.e10.

[35] Salzman J, Chen RE, Olsen MN, Wang PL, Brown PO. Cell-type specific features of circular RNA expression. PLoS Genet 2013;9(9):e1003777. 链接1

[36] Guarnerio J, Bezzi M, Jeong JC, Paffenholz SV, Berry K, Naldini MM, et al. Oncogenic role of fusion-circRNAs derived from cancer-associated chromosomal translocations. Cell 2016;165(2):289‒302. 链接1

[37] Conn SJ, Pillman KA, Toubia J, Conn VM, Salmanidis M, Phillips CA, et al. The RNA binding protein quaking regulates formation of circRNAs. Cell 2015;160(6):1125‒34. 链接1

[38] Coulie PG, Lehmann F, Lethé B, Herman J, Lurquin C, Andrawiss M, et al. A mutated intron sequence codes for an antigenic peptide recognized by cytolytic T lymphocytes on a human melanoma. Proc Natl Acad Sci USA 1995;92(17):7976‒80. 链接1

[39] Wang RF, Parkhurst MR, Kawakami Y, Robbins PF, Rosenberg SA. Utilization of an alternative open reading frame of a normal gene in generating a novel human cancer antigen. J Exp Med 1996;183(3):1131‒40. 链接1

[40] Michaux A, Larrieu P, Stroobant V, Fonteneau JF, Jotereau F, van den Eynde BJ, et al. A spliced antigenic peptide comprising a single spliced amino acid is produced in the proteasome by reverse splicing of a longer peptide fragment followed by trimming. J Immunol 2014;192(4):1962‒71. 链接1

[41] Smart AC, Margolis CA, Pimentel H, He MX, Miao D, Adeegbe D, et al. Intron retentionisa source ofneoepitopes incancer.NatBiotechnol2018;36(11):1056‒8. 链接1

[42] Hanada K, Yewdell JW, Yang JC. Immune recognition of a human renal cancer antigen through post-translational protein splicing. Nature 2004;427(6971):252‒6. 链接1

[43] Xiang R, Ma L, Yang M, Zheng Z, Chen X, Jia F, et al. Increased expression of peptides from non-coding genes in cancer proteomics datasets suggests potential tumor neoantigens. Commun Biol 2021;4(1):496. 链接1

[44] Kote S, Pirog A, Bedran G, Alfaro J, Dapic I. Mass spectrometry-based identification of MHC-associated peptides. Cancers 2020;12(3):12. 链接1

[45] Bassani-Sternberg M, Pletscher-Frankild S, Jensen LJ, Mann M. Mass spectrometry of human leukocyte antigen class I peptidomes reveals strong effects of protein abundance and turnover on antigen presentation. Mol Cell Proteomics 2015;14(3):658‒73. 链接1

[46] Abelin JG, Keskin DB, Sarkizova S, Hartigan CR, Zhang W, Sidney J, et al. Mass spectrometry profiling of HLA-associated peptidomes in mono-allelic cells enables more accurate epitope prediction. Immunity 2017;46(2):315‒26. 链接1

[47] Wilhelm M, Schlegl J, Hahne H, Gholami AM, Lieberenz M, Savitski MM, et al. Mass-spectrometry-based draft of the human proteome. Nature 2014;509(7502):582‒7. 链接1

[48] Liu T, Tan J, Wu M, Fan W, Wei J, Zhu B, et al. High-affinity neoantigens correlate with better prognosis and trigger potent antihepatocellular carcinoma (HCC) activity by activating CD39+CD8+ T cells. Gut 2021;70(10):1965‒77. 链接1

[49] Shi R, Tang YQ, Miao H. Metabolism in tumor microenvironment: implications for cancer immunotherapy. MedComm 2020;1(1):47‒68. 链接1

相关研究