Immune signature profiling identified prognostic factors for gastric cancer
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摘要
Objective: Tumor microenvironment, especially the host immune system, plays a pivotal role in tumor initiation and progression. Profiling of immune signature within tumor might uncover biomarkers for targeted therapies and clinical outcomes. However, systematic analysis of immune-related genes in gastric cancer(GC) has not been reported.Methods: Expressions of a total of 718 immune-related genes were generated in 372 stomach adenocarcinoma(STAD) patients from The Cancer Genome Atlas(TCGA) database using RNA-sequencing data. Integrated bioinformatics analyses were performed to identify prognostic factors as well.Results: Survival analyses revealed 73 genes, which were significantly associated with patient's overall survival(OS). Taken together with clinicopathological parameters, we established a predictive model, containing 10 immune-related genes, which were NRP1, C6, CXCR4, LBP, PNMA1, TLR5, ITGA6, MICB, PBK and TNFRSF18,with powerful efficiency in distinguishing satisfactory or poor survival of STAD patients. Moreover, the top 3 ranked prognostic genes, NRP1, TGFβ2 and MFGE8, were also significantly associated with patient's OS by an independent validation achieved from Kaplan-Meier plotter database.Conclusions: We profiled prognostic immune signature and established prognostic predictive model for GC,which could reflect immune disorders within tumor microenvironment, and also may provide novel predictive and therapeutic targets for GC patients in the near future.
Objective: Tumor microenvironment, especially the host immune system, plays a pivotal role in tumor initiation and progression. Profiling of immune signature within tumor might uncover biomarkers for targeted therapies and clinical outcomes. However, systematic analysis of immune-related genes in gastric cancer(GC) has not been reported.Methods: Expressions of a total of 718 immune-related genes were generated in 372 stomach adenocarcinoma(STAD) patients from The Cancer Genome Atlas(TCGA) database using RNA-sequencing data. Integrated bioinformatics analyses were performed to identify prognostic factors as well.Results: Survival analyses revealed 73 genes, which were significantly associated with patient's overall survival(OS). Taken together with clinicopathological parameters, we established a predictive model, containing 10 immune-related genes, which were NRP1, C6, CXCR4, LBP, PNMA1, TLR5, ITGA6, MICB, PBK and TNFRSF18,with powerful efficiency in distinguishing satisfactory or poor survival of STAD patients. Moreover, the top 3 ranked prognostic genes, NRP1, TGFβ2 and MFGE8, were also significantly associated with patient's OS by an independent validation achieved from Kaplan-Meier plotter database.Conclusions: We profiled prognostic immune signature and established prognostic predictive model for GC,which could reflect immune disorders within tumor microenvironment, and also may provide novel predictive and therapeutic targets for GC patients in the near future.
Objective: Tumor microenvironment, especially the host immune system, plays a pivotal role in tumor initiation and progression. Profiling of immune signature within tumor might uncover biomarkers for targeted therapies and clinical outcomes. However, systematic analysis of immune-related genes in gastric cancer(GC) has not been reported.Methods: Expressions of a total of 718 immune-related genes were generated in 372 stomach adenocarcinoma(STAD) patients from The Cancer Genome Atlas(TCGA) database using RNA-sequencing data. Integrated bioinformatics analyses were performed to identify prognostic factors as well.Results: Survival analyses revealed 73 genes, which were significantly associated with patient's overall survival(OS). Taken together with clinicopathological parameters, we established a predictive model, containing 10 immune-related genes, which were NRP1, C6, CXCR4, LBP, PNMA1, TLR5, ITGA6, MICB, PBK and TNFRSF18,with powerful efficiency in distinguishing satisfactory or poor survival of STAD patients. Moreover, the top 3 ranked prognostic genes, NRP1, TGFβ2 and MFGE8, were also significantly associated with patient's OS by an independent validation achieved from Kaplan-Meier plotter database.Conclusions: We profiled prognostic immune signature and established prognostic predictive model for GC,which could reflect immune disorders within tumor microenvironment, and also may provide novel predictive and therapeutic targets for GC patients in the near future.
引文
1.Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin 2016;66:115-32.
2 .Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.
3 .Yang L, Zheng R, Wang N, et al. Incidence and mortality of stomach cancer in China, 2014. Chin J Cancer Res 2018;30:291-8.
4 .Fridman WH, Mlecnik B, Bindea G, et al.Immunosurveillance in human non-viral cancers.Curr Opin Immunol 2011;23:272-8.
5 .Hanahan D, Weinberg RA. Hallmarks of cancer:the next generation. Cell 2011;144:646-74.
6 .Klein G, Klein E. Surveillance against tumors—is it mainly immunological? Immunol Lett 2005;100:29-33.
7 .Merelli B, Massi D, Cattaneo L, et al. Targeting the PD1/PD-L1 axis in melanoma:biological rationale,clinical challenges and opportunities. Crit Rev Oncol Hematol 2014;89:140-65.
8 .Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab(anti-PD-1)in melanoma. N Engl J Med 2013;369:134-44.
9 .Topalian SL, Hodi FS, Brahmer JR, et al. Safety,activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-54.
10 .Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-65.
11 .Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens(ONO-4538-12 , ATTRACTION-2):a randomised, double-blind,placebo-controlled, phase 3 trial. Lancet 2017;390:2461-71.
12 .Taieb J, Moehler M, Boku N, et al. Evolution of checkpoint inhibitors for the treatment of metastatic gastric cancers:Current status and future perspectives.Cancer Treat Rev 2018;66:104-13.
13 .Ralph C, Elkord E, Burt DJ, et al. Modulation of lymphocyte regulation for cancer therapy:a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin Cancer Res 2010;16:1662-72.
14 .Bilgin B, Sendur MA, Bülent Ak?nc?M, et al.Targeting the PD-1 pathway:a new hope for gastrointestinal cancers. Curr Med Res Opin 2017;33:749-59.
15 .Thompson ED, Zahurak M, Murphy A, et al. Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma. Gut 2017;66:794-801.
16 .Kim JW, Nam KH, Ahn SH, et al. Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer.Gastric Cancer 2016;19:42-52.
17 .Zhuang Y, Peng LS, Zhao YL, et al. CD8(+)T cells that produce interleukin-17 regulate myeloid-derived suppressor cells and are associated with survival time of patients with gastric cancer. Gastroenterology2012;143:951-62.
18 .Coussens LM, Werb Z. Inflammation and cancer.Nature 2002;420:860-7.
19 .Gentles AJ, Newman AM, Liu CL, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med 2015;21:938-45.
20 .Tarhini AA, Lin Y, Lin HM, et al. Expression profiles of immune-related genes are associated with neoadjuvant ipilimumab clinical benefit. Oncoimmunology2016;6:e1231291.
21 .Maccalli C, Giannarelli D, Capocefalo F, et al.Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study.Oncoimmunology 2015;5:e1071007.
22 .Li Y, Lu Z, Che Y, et al. Immune signature profiling identified predictive and prognostic factors for esophageal squamous cell carcinoma. Oncoimmunology2017;6:e1356147.
23 .Mahajan UM, Langhoff E, Goni E, et al. Immune cell and stromal signature associated with progression-free survival of patients with resected pancreatic ductal adenocarcinoma. Gastroenterology 2018;155:1625-39.
24 .Shen S, Wang G, Zhang R, et al. Development and validation of an immune gene-set based Prognostic signature in ovarian cancer. EBio Medicine 2019;40:318-26.
25 .Li B, Cui Y, Diehn M, et al. Development and validation of an individualized immune prognostic signature in early-stage nonsquamous non-small cell lung cancer. JAMA Oncol 2017;3:1529-37.
26 .Montojo J, Zuberi K, Rodriguez H, et al.Gene MANIA Cytoscape plugin:fast gene function predictions on the desktop. Bioinformatics 2010;26:2927-8.
27 .Heagerty PJ, Lumley T, Pepe MS. Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics 2000;56:337-44.
28 .Szász AM, Lánczky A, Nagyá, et al. Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients. Oncotarget2016;7:49322-33.
29 .Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature 2001;411:375-9.
30 .Wang TT, Zhao YL, Peng LS, et al. Tumouractivated neutrophils in gastric cancer foster immune suppression and disease progression through GMCSF-PD-L1 pathway. Gut 2017;66:1900-11.
31 .Cheng W, Ren X, Zhang C, et al. Bioinformatic profiling identifies an immune-related risk signature for glioblastoma. Neurology 2016;86:2226-34.
32 .Li L, Jiang X, Zhang Q, et al. Neuropilin-1 is associated with clinicopathology of gastric cancer and contributes to cell proliferation and migration as multifunctional co-receptors. J Exp Clin Cancer Res2016;35:16.
33 .Shen Z, Kauttu T, Cao J, et al. Macrophage coculture enhanced invasion of gastric cancer cells via TGF-βand BMP pathways. Scand J Gastroenterol 2013;48:466-72.
34 .Ma GF, Miao Q, Zeng XQ, et al. Transforming growth factor-β1 and-β2 in gastric precancer and cancer and roles in tumor-cell interactions with peripheral blood mononuclear cells in vitro. PLo S One 2013;8:e54249.
35 .An SY, Jang YJ, Lim HJ, et al. Milk fat globule-EGF factor 8, secreted by mesenchymal stem cells, protects against liver fibrosis in mice. Gastroenterology 2017;152:1174-86.
36 .Zhao S, Wang H, Nie Y, et al. Midkine upregulates MICA/B expression in human gastric cancer cells and decreases natural killer cell cytotoxicity. Cancer Immunol Immunother 2012;61:1745-53.
37 .Garrido-Tapia M, Hernández CJ, Ascui G, et al.STAT3 inhibition by STA21 increases cell surface expression of MICB and the release of soluble MICB by gastric adenocarcinoma cells. Immunobiology2017;222:1043-51.
38 .Izumi D, Ishimoto T, Miyake K, et al.CXCL12/CXCR4 activation by cancer-associated fibroblasts promotes integrinβ1 clustering and invasiveness in gastric cancer. Int J Cancer 2016;138:1207-19.
39 .Xiang Z, Zhou ZJ, Xia GK, et al. A positive crosstalk between CXCR4 and CXCR2 promotes gastric cancer metastasis. Oncogene 2017;36:5122-33.
2 .Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.
3 .Yang L, Zheng R, Wang N, et al. Incidence and mortality of stomach cancer in China, 2014. Chin J Cancer Res 2018;30:291-8.
4 .Fridman WH, Mlecnik B, Bindea G, et al.Immunosurveillance in human non-viral cancers.Curr Opin Immunol 2011;23:272-8.
5 .Hanahan D, Weinberg RA. Hallmarks of cancer:the next generation. Cell 2011;144:646-74.
6 .Klein G, Klein E. Surveillance against tumors—is it mainly immunological? Immunol Lett 2005;100:29-33.
7 .Merelli B, Massi D, Cattaneo L, et al. Targeting the PD1/PD-L1 axis in melanoma:biological rationale,clinical challenges and opportunities. Crit Rev Oncol Hematol 2014;89:140-65.
8 .Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab(anti-PD-1)in melanoma. N Engl J Med 2013;369:134-44.
9 .Topalian SL, Hodi FS, Brahmer JR, et al. Safety,activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-54.
10 .Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-65.
11 .Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens(ONO-4538-12 , ATTRACTION-2):a randomised, double-blind,placebo-controlled, phase 3 trial. Lancet 2017;390:2461-71.
12 .Taieb J, Moehler M, Boku N, et al. Evolution of checkpoint inhibitors for the treatment of metastatic gastric cancers:Current status and future perspectives.Cancer Treat Rev 2018;66:104-13.
13 .Ralph C, Elkord E, Burt DJ, et al. Modulation of lymphocyte regulation for cancer therapy:a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin Cancer Res 2010;16:1662-72.
14 .Bilgin B, Sendur MA, Bülent Ak?nc?M, et al.Targeting the PD-1 pathway:a new hope for gastrointestinal cancers. Curr Med Res Opin 2017;33:749-59.
15 .Thompson ED, Zahurak M, Murphy A, et al. Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma. Gut 2017;66:794-801.
16 .Kim JW, Nam KH, Ahn SH, et al. Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer.Gastric Cancer 2016;19:42-52.
17 .Zhuang Y, Peng LS, Zhao YL, et al. CD8(+)T cells that produce interleukin-17 regulate myeloid-derived suppressor cells and are associated with survival time of patients with gastric cancer. Gastroenterology2012;143:951-62.
18 .Coussens LM, Werb Z. Inflammation and cancer.Nature 2002;420:860-7.
19 .Gentles AJ, Newman AM, Liu CL, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med 2015;21:938-45.
20 .Tarhini AA, Lin Y, Lin HM, et al. Expression profiles of immune-related genes are associated with neoadjuvant ipilimumab clinical benefit. Oncoimmunology2016;6:e1231291.
21 .Maccalli C, Giannarelli D, Capocefalo F, et al.Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study.Oncoimmunology 2015;5:e1071007.
22 .Li Y, Lu Z, Che Y, et al. Immune signature profiling identified predictive and prognostic factors for esophageal squamous cell carcinoma. Oncoimmunology2017;6:e1356147.
23 .Mahajan UM, Langhoff E, Goni E, et al. Immune cell and stromal signature associated with progression-free survival of patients with resected pancreatic ductal adenocarcinoma. Gastroenterology 2018;155:1625-39.
24 .Shen S, Wang G, Zhang R, et al. Development and validation of an immune gene-set based Prognostic signature in ovarian cancer. EBio Medicine 2019;40:318-26.
25 .Li B, Cui Y, Diehn M, et al. Development and validation of an individualized immune prognostic signature in early-stage nonsquamous non-small cell lung cancer. JAMA Oncol 2017;3:1529-37.
26 .Montojo J, Zuberi K, Rodriguez H, et al.Gene MANIA Cytoscape plugin:fast gene function predictions on the desktop. Bioinformatics 2010;26:2927-8.
27 .Heagerty PJ, Lumley T, Pepe MS. Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics 2000;56:337-44.
28 .Szász AM, Lánczky A, Nagyá, et al. Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients. Oncotarget2016;7:49322-33.
29 .Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature 2001;411:375-9.
30 .Wang TT, Zhao YL, Peng LS, et al. Tumouractivated neutrophils in gastric cancer foster immune suppression and disease progression through GMCSF-PD-L1 pathway. Gut 2017;66:1900-11.
31 .Cheng W, Ren X, Zhang C, et al. Bioinformatic profiling identifies an immune-related risk signature for glioblastoma. Neurology 2016;86:2226-34.
32 .Li L, Jiang X, Zhang Q, et al. Neuropilin-1 is associated with clinicopathology of gastric cancer and contributes to cell proliferation and migration as multifunctional co-receptors. J Exp Clin Cancer Res2016;35:16.
33 .Shen Z, Kauttu T, Cao J, et al. Macrophage coculture enhanced invasion of gastric cancer cells via TGF-βand BMP pathways. Scand J Gastroenterol 2013;48:466-72.
34 .Ma GF, Miao Q, Zeng XQ, et al. Transforming growth factor-β1 and-β2 in gastric precancer and cancer and roles in tumor-cell interactions with peripheral blood mononuclear cells in vitro. PLo S One 2013;8:e54249.
35 .An SY, Jang YJ, Lim HJ, et al. Milk fat globule-EGF factor 8, secreted by mesenchymal stem cells, protects against liver fibrosis in mice. Gastroenterology 2017;152:1174-86.
36 .Zhao S, Wang H, Nie Y, et al. Midkine upregulates MICA/B expression in human gastric cancer cells and decreases natural killer cell cytotoxicity. Cancer Immunol Immunother 2012;61:1745-53.
37 .Garrido-Tapia M, Hernández CJ, Ascui G, et al.STAT3 inhibition by STA21 increases cell surface expression of MICB and the release of soluble MICB by gastric adenocarcinoma cells. Immunobiology2017;222:1043-51.
38 .Izumi D, Ishimoto T, Miyake K, et al.CXCL12/CXCR4 activation by cancer-associated fibroblasts promotes integrinβ1 clustering and invasiveness in gastric cancer. Int J Cancer 2016;138:1207-19.
39 .Xiang Z, Zhou ZJ, Xia GK, et al. A positive crosstalk between CXCR4 and CXCR2 promotes gastric cancer metastasis. Oncogene 2017;36:5122-33.