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Identification of immune-related signature with prognosis in children with stage 4 and 4S neuroblastoma

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Abstract

Objective

Spontaneous regression of tumors is an attractive phenomenon that most commonly occurs in stage 4S neuroblastoma (NB). However, the mechanism underlying this phenomenon remains unclear.

Methods

Datasets correlated with NB were downloaded from online public databases, the differentially expressed genes (DEGs) between stage 4 and 4S associated with immunity were identified, and functional enrichment analysis was utilized to explore the potential functions and signaling pathways of these DEGs. In addition, based on these DEGs, a prognostic signature was constructed and validated, and differences in immune cell infiltration were analyzed.

Results

A total of 13 DEGs were finally identified, and functional enrichment analysis revealed that these DEGs were primarily enriched in the positive regulation of neuron differentiation and TGF-β signaling pathway. The signature successfully stratifies patients into two risk score groups and performs well in judging prognosis and predicting overall survival time. In addition, the prognostic value of the risk score calculated by the signature was independent of clinical factors. The results of immune cell infiltration showed that patients with a high infiltration of resting CD4 + memory T cells had a better prognosis, while plasma cells had a worse prognosis.

Conclusion

The results of the functional enrichment analysis of these identified DEGs suggested that these DEGs may be related to spontaneous regression of NB. In addition, the prognostic signature has the potential to create new risk stratification in patients with NB.

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Availability of data and materials

The data that support the findings of this study were obtained from online public databases, which are publicly available as they were uploaded by the authors.

References

  1. Pezzolo A, Parodi F, Corrias MV, Cinti R, Gambini C, Pistoia V. Tumor origin of endothelial cells in human neuroblastoma. J Clin Oncol. 2007;25(4):376–83.

    Article  CAS  PubMed  Google Scholar 

  2. Tsubota S, Kadomatsu K. Origin and initiation mechanisms of neuroblastoma. Cell Tissue Res. 2018;372:211–21.

    Article  CAS  PubMed  Google Scholar 

  3. Hörmann M. Neuroblastoma in children. Radiologe. 2008;48:940–5.

    Article  PubMed  Google Scholar 

  4. Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010;362:2202–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ishola TA, Chung DH. Neuroblastoma. Surg Oncol. 2007;16:149–56.

    Article  PubMed  Google Scholar 

  6. Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993;11(8):1466–77.

    Article  CAS  PubMed  Google Scholar 

  7. Ide Smith E, Haase GM, Seeger RC, Brodeur GM. A surgical perspective on the current staging in neuroblastoma—the International Neuroblastoma Staging System proposal. J Pediatr Surg. 1989;24(4):386–90.

    Article  Google Scholar 

  8. Ikeda H, Iehara T, Tsuchida Y, Kaneko M, Hata J, Naito H, et al. Experience with International Neuroblastoma Staging System and pathology classification. Br J Cancer. 2002;86(7):1110–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Papac RJ. Spontaneous regression of cancer. Cancer Treat Rev. 1996;22:395–423.

    Article  CAS  PubMed  Google Scholar 

  10. Brodeur GM. Spontaneous regression of neuroblastoma. Cell Tissue Res. 2018;372:277–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Papac RJ. Spontaneous regression of cancer: possible mechanisms. In Vivo (Athens, Greece). 1998;12:571–8.

    CAS  PubMed  Google Scholar 

  12. Challis GB, Stam HJ. The spontaneous regression of cancer. a review of cases from 1900 to 1987. Acta Oncol (Stockholm, Sweden). 1990;29:545–50.

    Article  CAS  Google Scholar 

  13. Meng X, Li H, Fang E, Feng J, Zhao X. Comparison of stage 4 and stage 4s neuroblastoma identifies autophagy-related gene and LncRNA Signatures Associated With Prognosis. Front Oncol. 2020;19(10):1411.

    Article  Google Scholar 

  14. Inoue J, Misawa A, Tanaka Y, Ichinose S, Sugino Y, Hosoi H, et al. Lysosomal-associated protein multispanning transmembrane 5 gene (LAPTM5) is associated with spontaneous regression of neuroblastomas. PLoS ONE. 2009;4(9): e7099.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kocak H, Ackermann S, Hero B, Kahlert Y, Oberthuer A, Juraeva D, et al. Hox-C9 activates the intrinsic pathway of apoptosis and is associated with spontaneous regression in neuroblastoma. Cell Death Dis. 2013;4(4): e586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Koizumi H, Wakisaka M, Nakada K, Takakuwa T, Fujioka T, Yamate N, et al. Demonstration of apoptosis in neuroblastoma and its relationship to tumour regression. Virchows Arch. 1995;427(2):167–73.

    Article  CAS  PubMed  Google Scholar 

  17. Parkin J, Cohen B. An overview of the immune system. Lancet. 2001;357(9270):1777–89.

    Article  CAS  PubMed  Google Scholar 

  18. Karmakar S, Reilly KM. The role of the immune system in neurofibromatosis type 1-associated nervous system tumors. CNS Oncol. 2017;6(1):45–60.

    Article  CAS  PubMed  Google Scholar 

  19. Lian X, Yang K, Li R, et al. Immunometabolic rewiring in tumorigenesis and anti-tumor immunotherapy. Mol Cancer. 2022;21(1):27.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008;27(45):5904–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gurney JG, Severson RK, Davis S, Robison LL. Incidence of cancer in children in the United States Sex-, race-, and 1-year age-specific rates by histologic type. Cancer. 1995;75(8):2186–95.

    Article  CAS  PubMed  Google Scholar 

  23. Al-Battashi A, Al-Rahbi A, Al-Rawahi A, Mamdouh M, Al-Ghaithi I, Ramadhan FA. Neuroblastoma among Omani Children: clinical characteristics and survival outcome from a dedicated centre. Sultan Qaboos Univ Med J. 2021;21(4):578–84.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Aygun N. Biological and genetic features of neuroblastoma and their clinical importance. Curr Pediatr Rev. 2018;14:73–90.

    Article  CAS  PubMed  Google Scholar 

  25. Gao XN, Tang SQ, Lin J. Clinical features and prognosis of advanced neuroblastoma in children]. Zhongguo dang dai er ke za zhi Chin J Contemp Pediatr. 2007;9:351–4.

    Google Scholar 

  26. Bhatnagar SN, Sarin YK. Neuroblastoma: a review of management and outcome. Indian J Pediatr. 2012;79:787–92.

    Article  PubMed  Google Scholar 

  27. Zhang Q, Wu X, Fan Y, Jiang P, Zhao Y, Yang Y, et al. Single-cell analysis reveals dynamic changes of neural cells in developing human spinal cord. EMBO Rep. 2021;22(11): e52728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wiszniak S, Schwarz Q. Notch signaling defines dorsal root ganglia neuroglial fate choice during early neural crest cell migration. BMC Neurosci. 2019;20:21.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ponzoni M, Bachetti T, Corrias MV, Brignole C, Pastorino F, Calarco E, et al. Recent advances in the developmental origin of neuroblastoma: an overview. J Exp Clin Cancer Res. 2022;41(1):92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Marayati R, Williams AP, Bownes LV, Quinn CH, Stewart JE, Mroczek-Musulman E, et al. Novel retinoic acid derivative induces differentiation and growth arrest in neuroblastoma. J Pediatr Surg. 2020;55(6):1072–80.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lonergan GJ, Schwab CM, Suarez ES, Carlson CL. Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma: radiologic-pathologic correlation. Radiographics. 2002;22(4):911–34.

    Article  PubMed  Google Scholar 

  32. Clark DA, Coker R. Transforming growth factor-beta (TGF-beta). Int J Biochem Cell Biol. 1998;30:293–8.

    Article  CAS  PubMed  Google Scholar 

  33. Syed V. TGF-β signaling in cancer. J Cell Biochem. 2016;117:1279–87.

    Article  CAS  PubMed  Google Scholar 

  34. Bierie B, Moses HL. TGF-beta and cancer. Cytokine Growth Factor Rev. 2006;17:29–40.

    Article  CAS  PubMed  Google Scholar 

  35. Sakaki-Yumoto M, Katsuno Y, Derynck R. TGF-β family signaling in stem cells. Biochem Biophys Acta. 1830;2013:2280–96.

    Google Scholar 

  36. Fei T, Chen YG. Regulation of embryonic stem cell self-renewal and differentiation by TGF-beta family signaling. Sci China Life Sci. 2010;53:497–503.

    Article  CAS  PubMed  Google Scholar 

  37. Zhao H, Wei J, Sun J. Roles of TGF-β signaling pathway in tumor microenvironment and cancer therapy. Int Immunopharmacol. 2020;89: 107101.

    Article  CAS  PubMed  Google Scholar 

  38. Yoshimura A, Muto G. TGF-β function in immune suppression. Curr Top Microbiol Immunol. 2011;350:127–47.

    CAS  PubMed  Google Scholar 

  39. Li S, Liu M, Do MH, Chou C, Stamatiades EG, Nixon BG, et al. Cancer immunotherapy via targeted TGF-β signalling blockade in TH cells. Nature. 2020;587(7832):121–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lebman DA, Edmiston JS. The role of TGF-beta in growth, differentiation, and maturation of B lymphocytes. Microbes Infect. 1999;1:1297–304.

    Article  CAS  PubMed  Google Scholar 

  41. Tsuchida Y, Sumitomo S, Ishigaki K, Suzuki A, Kochi Y, Tsuchiya H, et al. TGF-β3 inhibits antibody production by human B cells. PLoS ONE. 2017;12(1): e0169646.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Taylor AW. Review of the activation of TGF-beta in immunity. J Leukoc Biol. 2009;85:29–33.

    Article  CAS  PubMed  Google Scholar 

  43. Viel S, Marçais A, Guimaraes FS, Loftus R, Rabilloud J, Grau M, et al. TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci Signal. 2016;9(415):ra9.

    Article  Google Scholar 

  44. Batlle E, Massagué J. Transforming growth factor-β signaling in immunity and cancer. Immunity. 2019;50:924–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mohammad NS, Nazli R, Zafar H, Fatima S. Effects of lipid based multiple micronutrients supplement on the birth outcome of underweight pre-eclamptic women: a randomized clinical trial. Pak J Med Sci. 2022;38(1):219–26.

    PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by Part of research grants from the Key Project of “Research on Prevention and Control of Major Chronic Non-Communicable Diseases”, the Ministry of Science and Technology of the People’s Republic of China, National Key R & D Program of China (No. 2018YFC1313000, 2018YFC1313004).

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Authors and Affiliations

  1. Department of Pediatric Surgical Oncology, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Children’s Hospital of Chongqing Medical University and the National Clinical Research Center for Child Health and Disorders, Chongqing, 400014, People’s Republic of China

    Lijian Cao, Qingqing Liu, Yue Ma & Shan Wang

Authors
  1. Lijian Cao
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  2. Qingqing Liu
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  3. Yue Ma
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  4. Shan Wang
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Contributions

SW was responsible for the overall conception and design of the study and revision of the manuscript. LJC performed most of the data analyses, and wrote the manuscript. QQL was responsible for technical guidance and preliminary modification of the manuscript. YM was responsible for the data sorting and partial analysis. All authors reviewed, edited, and approved the manuscript.

Corresponding author

Correspondence to Shan Wang.

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This study did not involve the approval of ethics and morality; therefore, written informed consent from the participants was not required.

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This study did not involve the approval of ethics and morality; therefore, written informed consent from the participants was not required.

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Cao, L., Liu, Q., Ma, Y. et al. Identification of immune-related signature with prognosis in children with stage 4 and 4S neuroblastoma. Clin Transl Oncol 26, 905–916 (2024). https://doi.org/10.1007/s12094-023-03320-4

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  • DOI: https://doi.org/10.1007/s12094-023-03320-4

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