肝癌免疫细胞浸润模式及与预后的相关性分析
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摘要
目的研究肝癌免疫细胞的浸润模式,探索免疫细胞浸润与预后的关系。方法从TCGA数据库下载肝细胞癌转录本数据及相关临床数据,通过Cibersort软件的反卷积法计算22种免疫细胞的占比。采用K-M生存分析Log-Rank法计算每种免疫细胞与生存的相关性。结果从TCGA数据库中得到基因转录本数据共424例,包含肝癌组织374例、正常肝组织50例。每个样本检测基因位点60483个,包含mRNA 19658个。数据校正后使用Cibersort软件"反卷积法"得到22种免疫细胞的占比数据,采用P<0.05筛选样本,得到肝细胞癌组织40例、正常肝组织2例。K-M生存分析显示活化的肥大细胞、未活化的自然杀伤细胞、嗜酸性粒细胞组成比例高者预后差,活化的自然杀伤细胞比例高者预后更好。结论肝癌中存在各类免疫细胞不同程度的浸润,浸润性免疫细胞可以作为影响肝癌患者预后的因素。
Objective To study the infiltration pattern of immune cells in hepatocellular carcinoma(HCC)and to explore the relationship between immune cells infiltration and prognosis.Methods Transcripts and clinical data of hepatocellular carcinoma were downloaded from TCGA database.The proportion of 22 kinds of immune cells was calculated by deconvolution method of Cibersort software.K-M survival analysis with Log-Rank method was used to calculate the correlation between each kind of immune cells and survival.Results Totally,424 transcripts of hepatocellular carcinoma were obtained from TCGA,including 374 hepatocellular carcinoma tissues and 50 normal liver tissues.Each sample detected 60483 genes,including 19658 mRNAs.After data correction,the proportion of 22 kinds of immune cells was obtained by deconvolution method with Cibersort software.Forty cases of hepatocellular carcinoma and 2 cases of normal liver tissue were obtained by screening samples with P<0.05.K-M survival analysis showed that the higher proportion of activated mast cells,inactivated natural killer cells and eosinophils were associated with worse prognosis,and the higher proportion of activated natural killer cells was associated with better prognosis.Conclusion There is infiltration of various kinds of immune cells in hepatocellular carcinoma,and infiltrating immune cells can serve as an factor affecting the prognosis of patients with hepatocellular carcinoma.
Objective To study the infiltration pattern of immune cells in hepatocellular carcinoma(HCC)and to explore the relationship between immune cells infiltration and prognosis.Methods Transcripts and clinical data of hepatocellular carcinoma were downloaded from TCGA database.The proportion of 22 kinds of immune cells was calculated by deconvolution method of Cibersort software.K-M survival analysis with Log-Rank method was used to calculate the correlation between each kind of immune cells and survival.Results Totally,424 transcripts of hepatocellular carcinoma were obtained from TCGA,including 374 hepatocellular carcinoma tissues and 50 normal liver tissues.Each sample detected 60483 genes,including 19658 mRNAs.After data correction,the proportion of 22 kinds of immune cells was obtained by deconvolution method with Cibersort software.Forty cases of hepatocellular carcinoma and 2 cases of normal liver tissue were obtained by screening samples with P<0.05.K-M survival analysis showed that the higher proportion of activated mast cells,inactivated natural killer cells and eosinophils were associated with worse prognosis,and the higher proportion of activated natural killer cells was associated with better prognosis.Conclusion There is infiltration of various kinds of immune cells in hepatocellular carcinoma,and infiltrating immune cells can serve as an factor affecting the prognosis of patients with hepatocellular carcinoma.
引文
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[2] Chen W,Zheng R,Baade P D,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
[3] Hainaut P,Plymoth A.Targeting the hallmarks of cancer:towards a rational approach to next-generation cancer therapy[J].Curr Opin Oncol,2013,25(1):50-51.
[4] Hanahan D,Weinberg R A.Hallmarks of cancer:the next generation[J].Cell,2011,144(5):646-674.
[5] Newman A M,Liu C L,Green M R,et al.Robust enumeration of cell subsets from tissue expression profiles[J].Nat Methods,2015,12(5):453-457.
[6] Gentles A J,Newman A M,Liu C L,et al.The prognostic landscape of genes and infiltrating immune cells across human cancers[J].Nat Med,2015,21(8):938-945.
[7] Rohr-Udilova N,Klinglmuller F,Schulte-Hermann R,et al.Deviations of the immune cell landscape between healthy liver and hepatocellular carcinoma[J].Sci Rep,2018,8(1):6220.
[8] Mantovani A,Allavena P,Sica A,et al.Cancer-related inflammation[J].Nature,2008,454(7203):436-444.
[9] Bronte V,Brandau S,Chen S H,et al.Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards[J].Nat Commun,2016,7:12150.
[10] Fridman W H,Pages F,Sautes-Fridman C,et al.The immune contexture in human tumours:impact on clinical outcome[J].Nat Rev Cancer,2012,12(4):298-306.
[11] Fridman W H,Zitvogel L,Sautes-Fridman C,et al.The immune contexture in cancer prognosis and treatment[J].Nat Rev Clin Oncol,2017,14(12):717-734.
[12] Mlecnik B,Bindea G,Angell H K,et al.Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability[J].Immunity,2016,44(3):698-711.
[13] Grabenbauer G G,Lahmer G,Distel L,et al.Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma[J].Clin Cancer Res,2006,12(11 Pt 1):3355-3360.
[14] Ladanyi A,Mohos A,Somlai B,et al.FOXP3+ cell density in primary tumor has no prognostic impact in patients with cutaneous malignant melanoma[J].Pathol Oncol Res,2010,16(3):303-309.
[15] Mahmoud S M,Paish E C,Powe D G,et al.An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer[J].Breast Cancer Res Treat,2011,127(1):99-108.
[16] Zhang Y L,Li J,Mo H Y,et al.Different subsets of tumor infiltrating lymphocytes correlate with NPC progression in different ways[J].Mol Cancer,2010,9:4.
[17] Tosolini M,Kirilovsky A,Mlecnik B,et al.Clinical impact of different classes of infiltrating T cytotoxic and helper cells(Th1,Th2,Treg,Th17)in patients with colorectal cancer[J].Cancer Res,2011,71(4):1263-1271.
[18] Winerdal M E,Marits P,Winerdal M,et al.FOXP3 and survival in urinary bladder cancer[J].BJU Int,2011,108(10):1672-1678.
[19] Leffers N,Gooden M J,De Jong R A,et al.Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer[J].Cancer Immunol Immunother,2009,58(3):449-459.
[20] 朱玲燕,周嘉,刘彦章,等.自然杀伤细胞在原发性肝细胞肝癌中的浸润及其与预后的关系[J].癌症,2009,28(11):1198-1202.
[21] Mantovani A.B cells and macrophages in cancer:yin and yang[J].Nat Med,2011,17(3):285-286.
[22] Olkhanud P B,Damdinsuren B,Bodogai M,et al.Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4(+)T cells to T-regulatory cells[J].Cancer Res,2011,71(10):3505-3515.
[23] 江敏,柳慧,吴丰华.姜黄素干预乳腺癌细胞诱导的巨噬细胞极化效应[J].华中科技大学学报:医学版,2018,47(2):131-135.
[24] Dilillo D J,Yanaba K,Tedder T F.B cells are required for optimal CD4+ and CD8+ T cell tumor immunity:therapeutic B cell depletion enhances B16 melanoma growth in mice[J].J Immunol,2010,184(7):4006-4016.
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