Cited by 160Sarcoma Diagnosis and TreatmentCancer Immunotherapy and BiomarkersImmune cells in cancer

Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of osteosarcoma

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Zhang, Chi, Zheng, Jing-Hui, Lin, Zong-Han, Lv, Hao-Yuan, Ye, Zhuo-Miao, Chen, Yue-Ping, Zhang, Xiao-Yun·2020·Aging

Abstract

This work aimed to investigate tumor-infiltrating immune cells (TIICs) and immune-associated genes in the tumor microenvironment of osteosarcoma. An algorithm known as ESTIMATE was applied for immune score assessment, and osteosarcoma cases were assigned to the high and low immune score groups. Immune-associated genes between these groups were compared, and an optimal immune-related risk model was built by Cox regression analyses. The deconvolution algorithm (referred to as CIBERSORT) was applied to assess 22 TIICs for their amounts in the osteosarcoma microenvironment. Osteosarcoma cases with high immune score had significantly improved outcome (P<0.01). The proportions of naive B cells and M0 macrophages were significantly lower in high immune score tissues compared with the low immune score group (P<0.05), while the amounts of M1 macrophages, M2 macrophages, and resting dendritic cells were significantly higher (P<0.05). Important immune-associated genes were determined to generate a prognostic model by Cox regression analysis. Interestingly, cases with high risk score had poor outcome (P<0.01). The areas under the curve (AUC) for the risk model in predicting 1, 3 and 5-year survival were 0.634, 0.781, and 0.809, respectively. Gene set enrichment analysis suggested immunosuppression in high-risk osteosarcoma patients, in association with poor outcome.

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  • In group with high immune scores, the quantity of resting DCs was significantly higher than that in the low immune score group, and the degree of DC activation was positively related with anti-tumor therapy response.

    “A study found that in group with high immune scores, the quantity of resting DCs was significantly higher than that in the low immune score group, and the degree of DC activation was positively related with anti-tumor therapy response [61].”

    From Advances on immunotherapy for osteosarcoma (2024) · cites this paper as [61]

    The Results section on immune-cell composition reports a significantly higher proportion of resting dendritic cells in high-immune-score osteosarcoma tissues (P=0.024). The Discussion only suggests that dendritic-cell activation may be associated with improved patient outcome; it does not establish a positive relationship between activation and response to antitumor therapy. The paper measures proportions, not absolute quantities. (LLM, conf=0.88)

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Research works printed but not linked: 52

  1. [1]Moriarity BS, Otto GM, Rahrmann EP, Rathe SK, Wolf NK, Weg MT, Manlove LA, LaRue RS, Temiz NA, Molyneux SD, Choi K, Holly KJ, Sarver AL, et al. A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis. Nat Genet. 2015; 47: 615– 24. 10.1038/ng.3293 25961939 PMC4767150 · DOI
  2. [2]Nie Z, Peng H. Osteosarcoma in patients below 25 years of age: an observational study of incidence, metastasis, treatment and outcomes. Oncol Lett. 2018; 16: 6502– 14. 10.3892/ol.2018.9453 30405789 PMC6202522 · DOI
  3. [3]Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018; 68: 7– 30. 10.3322/caac.21442 29313949 · DOI
  4. [4]Isakoff MS, Bielack SS, Meltzer P, Gorlick R. Osteosarcoma: Current Treatment and a Collaborative Pathway to Success. J Clin Oncol. 2015; 33: 3029– 35. 10.1200/JCO.2014.59.4895 26304877 PMC4979196 · DOI
  5. [5]Liu Y, Qiao L, Zhang S, Wan G, Chen B, Zhou P, Zhang N, Wang Y. Dual pH-responsive multifunctional nanoparticles for targeted treatment of breast cancer by combining immunotherapy and chemotherapy. Acta Biomater. 2018; 66: 310– 24. 10.1016/j.actbio.2017.11.010 29129789 · DOI
  6. [6]Guerra AD, Yeung OW, Qi X, Kao WJ, Man K. The Anti-Tumor Effects of M1 Macrophage-Loaded Poly (ethylene glycol) and Gelatin-Based Hydrogels on Hepatocellular Carcinoma. Theranostics. 2017; 7: 3732– 44. 10.7150/thno.20251 29109772 PMC5667344 · DOI
  7. [8]Cortini M, Avnet S, Baldini N. Mesenchymal stroma: role in osteosarcoma progression. Cancer Lett. 2017; 405: 90– 99. 10.1016/j.canlet.2017.07.024 28774797 · DOI · Paper page
  8. [9]Wang C, Zhou X, Li W, Li M, Tu T, Ba X, Wu Y, Huang Z, Fan G, Zhou G, Wu S, Zhao J, Zhang J, Chen J. Macrophage migration inhibitory factor promotes osteosarcoma growth and lung metastasis through activating the RAS/MAPK pathway. Cancer Lett. 2017; 403: 271– 79. 10.1016/j.canlet.2017.06.011 28642171 · DOI
  9. [11]Yoshihara K, Shahmoradgoli M, Martínez E, Vegesna R, Kim H, Torres-Garcia W, Treviño V, Shen H, Laird PW, Levine DA, Carter SL, Getz G, Stemke-Hale K, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013; 4: 2612. 10.1038/ncomms3612 24113773 PMC3826632 · DOI · Paper page
  10. [12]Jia D, Li S, Li D, Xue H, Yang D, Liu Y. Mining TCGA database for genes of prognostic value in glioblastoma microenvironment. Aging (Albany NY). 2018; 10: 592– 605. 10.18632/aging.101415 29676997 PMC5940130 · DOI
  11. [13]Xu WH, Xu Y, Wang J, Wan FN, Wang HK, Cao DL, Shi GH, Qu YY, Zhang HL, Ye DW. Prognostic value and immune infiltration of novel signatures in clear cell renal cell carcinoma microenvironment. Aging (Albany NY). 2019; 11: 6999– 7020. 10.18632/aging.102233 31493764 PMC6756904 · DOI
  12. [14]Chen B, Khodadoust MS, Liu CL, Newman AM, Alizadeh AA. Profiling Tumor Infiltrating Immune Cells with CIBERSORT. Methods Mol Biol. 2018; 1711: 243– 59. 10.1007/978-1-4939-7493-1_12 29344893 PMC5895181 · DOI
  13. [15]Zeng D, Zhou R, Yu Y, Luo Y, Zhang J, Sun H, Bin J, Liao Y, Rao J, Zhang Y, Liao W. Gene expression profiles for a prognostic immunoscore in gastric cancer. Br J Surg. 2018; 105: 1338– 48. 10.1002/bjs.10871 29691839 PMC6099214 · DOI
  14. [16]Xiong Y, Wang K, Zhou H, Peng L, You W, Fu Z. Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression-based study. Cancer Med. 2018; 7: 4496– 508. 10.1002/cam4.1745 30117315 PMC6144159 · DOI
  15. [17]Ali HR, Chlon L, Pharoah PD, Markowetz F, Caldas C. Patterns of Immune Infiltration in Breast Cancer and Their Clinical Implications: A Gene-Expression-Based Retrospective Study. PLoS Med. 2016; 13: e1002194. 10.1371/journal.pmed.1002194 27959923 PMC5154505 · DOI
  16. [18]Li X, Chen Y, Liu X, Zhang J, He X, Teng G, Yu D. Tim3/Gal9 interactions between T cells and monocytes result in an immunosuppressive feedback loop that inhibits Th1 responses in osteosarcoma patients. Int Immunopharmacol. 2017; 44: 153– 59. 10.1016/j.intimp.2017.01.006 28103502 · DOI
  17. [20]Yang X, Shi Y, Li M, Lu T, Xi J, Lin Z, Jiang W, Guo W, Zhan C, Wang Q. Identification and validation of an immune cell infiltrating score predicting survival in patients with lung adenocarcinoma. J Transl Med. 2019; 17: 217. 10.1186/s12967-019-1964-6 31286969 PMC6615164 · DOI
  18. [21]Peng D, Wang L, Li H, Cai C, Tan Y, Xu B, Le H. An immune infiltration signature to predict the overall survival of patients with colon cancer. IUBMB Life. 2019; 71: 1760– 70. 10.1002/iub.2124 31301220 · DOI
  19. [22]Gomez-Brouchet A, Illac C, Gilhodes J, Bouvier C, Aubert S, Guinebretiere JM, Marie B, Larousserie F, Entz-Werlé N, de Pinieux G, Filleron T, Minard V, Minville V, et al. CD163-positive tumor-associated macrophages and CD8-positive cytotoxic lymphocytes are powerful diagnostic markers for the therapeutic stratification of osteosarcoma patients: an immunohistochemical analysis of the biopsies fromthe French OS2006 phase 3 trial. OncoImmunology. 2017; 6: e1331193. 10.1080/2162402X.2017.1331193 28932633 PMC5599091 · DOI
  20. [23]Buddingh EP, Kuijjer ML, Duim RA, Bürger H, Agelopoulos K, Myklebost O, Serra M, Mertens F, Hogendoorn PC, Lankester AC, Cleton-Jansen AM. Tumor-infiltrating macrophages are associated with metastasis suppression in high-grade osteosarcoma: a rationale for treatment with macrophage activating agents. Clin Cancer Res. 2011; 17: 2110– 19. 10.1158/1078-0432.CCR-10-2047 21372215 · DOI · Paper page
  21. [25]Zanganeh S, Hutter G, Spitler R, Lenkov O, Mahmoudi M, Shaw A, Pajarinen JS, Nejadnik H, Goodman S, Moseley M, Coussens LM, Daldrup-Link HE. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat Nanotechnol. 2016; 11: 986– 94. 10.1038/nnano.2016.168 27668795 PMC5198777 · DOI · Paper page
  22. [26]Zhou Q, Xian M, Xiang S, Xiang D, Shao X, Wang J, Cao J, Yang X, Yang B, Ying M, He Q. All-Trans Retinoic Acid Prevents Osteosarcoma Metastasis by Inhibiting M2 Polarization of Tumor-Associated Macrophages. Cancer Immunol Res. 2017; 5: 547– 59. 10.1158/2326-6066.CIR-16-0259 28515123 · DOI
  23. [27]Kawano M, Tanaka K, Itonaga I, Iwasaki T, Miyazaki M, Ikeda S, Tsumura H. Dendritic cells combined with anti-GITR antibody produce antitumor effects in osteosarcoma. Oncol Rep. 2015; 34: 1995– 2001. 10.3892/or.2015.4161 26239052 · DOI · Paper page
  24. [28]He YT, Zhang QM, Kou QC, Tang B. In vitro generation of cytotoxic T lymphocyte response using dendritic cell immunotherapy in osteosarcoma. Oncol Lett. 2016; 12: 1101– 06. 10.3892/ol.2016.4714 27446401 PMC4950224 · DOI · Paper page
  25. [29]Kawano M, Tanaka K, Itonaga I, Iwasaki T, Miyazaki M, Ikeda S, Tsumura H. Dendritic cells combined with doxorubicin induces immunogenic cell death and exhibits antitumor effects for osteosarcoma. Oncol Lett. 2016; 11: 2169– 75. 10.3892/ol.2016.4175 26998143 PMC4774596 · DOI
  26. [30]Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 2014; 15: e257– 67. 10.1016/S1470-2045(13)70585-0 24872109 · DOI
  27. [31]de Bruijn S, Anguille S, Verlooy J, Smits EL, van Tendeloo VF, de Laere M, Norga K, Berneman ZN, Lion E. Dendritic Cell-Based and Other Vaccination Strategies for Pediatric Cancer. Cancers (Basel). 2019; 11: 11. 10.3390/cancers11091396 31546858 PMC6770385 · DOI
  28. [32]Lehrke M, Lazar MA. The many faces of PPARgamma. Cell. 2005; 123: 993– 99. 10.1016/j.cell.2005.11.026 16360030 · DOI
  29. [33]Ding H, Chen Y, Qiu H, Liu C, Wang Y, Kang M, Tang W. PPARG c.1347C>T polymorphism is associated with cancer susceptibility: from a case-control study to a meta-analysis. Oncotarget. 2017; 8: 102277– 90. 10.18632/oncotarget.20925 29254243 PMC5731953 · DOI
  30. [34]Wu Y, Song T, Liu M, He Q, Chen L, Liu Y, Ni D, Liu J, Hu Y, Gu Y, Li Q, Zhou Q, Xie Y. PPARG Negatively Modulates Six2 in Tumor Formation of Clear Cell Renal Cell Carcinoma. DNA Cell Biol. 2019; 38: 700– 07. 10.1089/dna.2018.4549 31090452 · DOI
  31. [35]Sabatino L, Fucci A, Pancione M, Carafa V, Nebbioso A, Pistore C, Babbio F, Votino C, Laudanna C, Ceccarelli M, Altucci L, Bonapace IM, Colantuoni V. UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression. Oncogene. 2012; 31: 5061– 72. 10.1038/onc.2012.3 22286757 · DOI
  32. [36]Tang KQ, Wang YN, Zan LS, Yang WC. miR-27a controls triacylglycerol synthesis in bovine mammary epithelial cells by targeting peroxisome proliferator-activated receptor gamma. J Dairy Sci. 2017; 100: 4102– 12. 10.3168/jds.2016-12264 28284697 · DOI
  33. [37]Ma G, Zhang C, Luo W, Zhao JL, Wang X, Qian Y. Construction of microRNA-messenger networks for human osteosarcoma. J Cell Physiol. 2019; 234: 14145– 53. 10.1002/jcp.28107 30666640 PMC13483061 · DOI
  34. [38]Ogino S, Shima K, Baba Y, Nosho K, Irahara N, Kure S, Chen L, Toyoda S, Kirkner GJ, Wang YL, Giovannucci EL, Fuchs CS. Colorectal cancer expression of peroxisome proliferator-activated receptor gamma (PPARG, PPARgamma) is associated with good prognosis. Gastroenterology. 2009; 136: 1242– 50. 10.1053/j.gastro.2008.12.048 19186181 PMC2663601 · DOI
  35. [39]Hsu HM, Chu CM, Chang YJ, Yu JC, Chen CT, Jian CE, Lee CY, Chiang YT, Chang CW, Chang YT. Six novel immunoglobulin genes as biomarkers for better prognosis in triple-negative breast cancer by gene co-expression network analysis. Sci Rep. 2019; 9: 4484. 10.1038/s41598-019-40826-w 30872752 PMC6418134 · DOI
  36. [40]Ledet EM, Hu X, Sartor O, Rayford W, Li M, Mandal D. Characterization of germline copy number variation in high-risk African American families with prostate cancer. Prostate. 2013; 73: 614– 23. 10.1002/pros.22602 23060098 · DOI
  37. [41]Bin Amer SM, Maqbool Z, Nirmal MS, Qattan AT, Hussain SS, Jeprel HA, Tulbah AM, Malik OA, Al-Tweigeri TA. Gene expression profiling in women with breast cancer in a Saudi population. Saudi Med J. 2008; 29: 507– 13. 18382789
  38. [42]Remmelink M, Mijatovic T, Gustin A, Mathieu A, Rombaut K, Kiss R, Salmon I, Decaestecker C. Identification by means of cDNA microarray analyses of gene expression modifications in squamous non-small cell lung cancers as compared to normal bronchial epithelial tissue. Int J Oncol. 2005; 26: 247– 58. 10.3892/ijo.26.1.247 15586247 · DOI
  39. [43]Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006; 3: 177– 85. 10.1016/j.cmet.2006.02.002 16517405 · DOI · Paper page
  40. [44]Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006; 3: 187– 97. 10.1016/j.cmet.2006.01.012 16517406 · DOI · Paper page
  41. [45]Dupuy F, Tabariès S, Andrzejewski S, Dong Z, Blagih J, Annis MG, Omeroglu A, Gao D, Leung S, Amir E, Clemons M, Aguilar-Mahecha A, Basik M, et al. PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer. Cell Metab. 2015; 22: 577– 89. 10.1016/j.cmet.2015.08.007 26365179 · DOI · Paper page
  42. [46]Liu Y, Wang J, Wu M, Wan W, Sun R, Yang D, Sun X, Ma D, Ying G, Zhang N. Down-regulation of 3-phosphoinositide-dependent protein kinase-1 levels inhibits migration and experimental metastasis of human breast cancer cells. Mol Cancer Res. 2009; 7: 944– 54. 10.1158/1541-7786.MCR-08-0368 19531564 · DOI
  43. [47]Fujiwara S, Kawano Y, Yuki H, Okuno Y, Nosaka K, Mitsuya H, Hata H. PDK1 inhibition is a novel therapeutic target in multiple myeloma. Br J Cancer. 2013; 108: 170– 78. 10.1038/bjc.2012.527 23321518 PMC3553526 · DOI
  44. [48]Zabkiewicz J, Pearn L, Hills RK, Morgan RG, Tonks A, Burnett AK, Darley RL. The PDK1 master kinase is over-expressed in acute myeloid leukemia and promotes PKC-mediated survival of leukemic blasts. Haematologica. 2014; 99: 858– 64. 10.3324/haematol.2013.096487 24334295 PMC4008098 · DOI
  45. [49]Arsenic R. Immunohistochemical analysis of PDK1 expression in breast cancer. Diagn Pathol. 2014; 9: 82. 10.1186/1746-1596-9-82 24739482 PMC4005628 · DOI
  46. [50]Li Z, Shen J, Chan MT, Wu WK. MicroRNA-379 suppresses osteosarcoma progression by targeting PDK1. J Cell Mol Med. 2017; 21: 315– 23. 10.1111/jcmm.12966 27781416 PMC5264134 · DOI
  47. [51]Fang A, Luo H, Liu L, Fan H, Zhou Y, Yao Y, Zhang Y. Identification of pyruvate dehydrogenase kinase 1 inhibitors with anti-osteosarcoma activity. Bioorg Med Chem Lett. 2017; 27: 5450– 53. 10.1016/j.bmcl.2017.10.073 29150396 · DOI
  48. [52]Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015; 43: e47. 10.1093/nar/gkv007 25605792 PMC4402510 · DOI · Paper page
  49. [53]Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015; 12: 453– 57. 10.1038/nmeth.3337 25822800 PMC4739640 · DOI · Paper page
  50. [54]Bhattacharya S, Andorf S, Gomes L, Dunn P, Schaefer H, Pontius J, Berger P, Desborough V, Smith T, Campbell J, Thomson E, Monteiro R, Guimaraes P, et al. ImmPort: disseminating data to the public for the future of immunology. Immunol Res. 2014; 58: 234– 39. 10.1007/s12026-014-8516-1 24791905 · DOI
  51. [55]Morris JK, Bestwick J, Wald NJ. Multiple-marker screening for Down’s syndrome: a method of assessing the statistical robustness of proposed tests. J Med Screen. 2008; 15: 55– 61. 10.1258/jms.2008.007105 18573771 · DOI
  52. [56]Burns RJ, Deschênes SS, Schmitz N. Associations between Depressive Symptoms and Social Support in Adults with Diabetes: Comparing Directionality Hypotheses with a Longitudinal Cohort. Ann Behav Med. 2016; 50: 348– 57. 10.1007/s12160-015-9760-x 26631086 · DOI

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Sorted by citations

Authors
Zhang, C., Zheng, J.-H., Lin, Z.-H., Lv, H.-Y., Ye, Z.-M., Chen, Y.-P., & Zhang, X.-Y.
Affiliations
  • Guangxi University of Chinese Medicine (CN)
  • Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, China
  • Hubei University of Chinese Medicine (CN)
  • Ruikang School of Clinical Medicine, Guangxi University of Chinese Medicine, Nanning 530001, China
  • Department of Orthopedics, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, China
Venue
Aging
Published
2020-02-09
Volume
12
Issue
4
Pages
3486-3501
ISSN
1945-4589 (ISSN-L)
OpenAlex
W3004974382
Cited by
160
References
5
Citations by year
2026: 7 · 2025: 13 · 2024: 22 · 2023: 28 · 2022: 29 · 2021: 48 · 2020: 12 · 2019: 1
FWCI
16.91
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Aging (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
osteosarcoma, tumor microenvironment, tumor-infiltrating immune cells, immune-related genes, immune score, prognostic risk model, macrophage polarization, M1/M2 macrophages, naive B cells, immunosuppression, survival prediction
MeSH terms
Algorithms, Bone Neoplasms, Humans, Macrophages, Prognosis, Osteosarcoma, Survival Rate, Databases, Factual, Lymphocytes, Tumor-Infiltrating, Gene Expression Profiling, Tumor Microenvironment

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