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MHC class I dysfunction of glioma stem cells escapes from CTL-mediated immune response via activation of Wnt/β-catenin signaling pathway

Oncogene volume 39, pages 1098–1111 (2020)Cite this article

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Abstract

Glioma stem cells (GSCs) decrease T cells cognition and evade systemic immunosurveillance via downregulations or defects of major histocompatibility complex class I (MHC-I) molecule and antigen-processing machinery (APM) components. Improvement of tumor surface antigens of GSCs may be effective strategy to trigger an adaptive immune response and activate cytotoxic T cells (CTLs) to eliminate glioma. In this study, our data indicated that downregulations of MHC-I and APM components expressions were associated with Wnt pathway activation in GSCs. Histone deacetylases (HDAC) inhibition improved MHC-I and APM components expressions, which could be partly reverted by Wnt pathway activation. Blocking CTLs-mediated killing decreased the anti-tumor effect of tumor lysate vaccine. The enhancement of T cells immune response resulting from HDAC inhibition was dependent on CTLs cognition on tumor antigens presented by upregulated MHC-I molecule in GSCs. These data suggest that suppression of stemness pathway may be effective for GSCs-based immunotherapy against immune-escaped tumors.

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References

  1. Wu A, Wei J, Kong LY, Wang Y, Priebe W, Qiao W, et al. Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro Oncol. 2010;12:1113–25.

    Article  CAS  Google Scholar 

  2. Morgan MA, Canman CE. Replication stress: An Achilles’ heel of glioma cancer stem-like cells. Cancer Res. 2018;78:6713–6.

    Article  CAS  Google Scholar 

  3. Lathia JD, Mack SC, Mulkearns-Hubert EE, Valentim CL, Rich JN. Cancer stem cells in glioblastoma. Genes Dev. 2015;29:1203–17.

    Article  CAS  Google Scholar 

  4. Alimonti J, Zhang QJ, Gabathuler R, Reid G, Chen SS, Jefferies WA. TAP expression provides a general method for improving the recognition of malignant cells in vivo. Nat Biotechnol. 2000;18:515–20.

    Article  CAS  Google Scholar 

  5. Di Tomaso T, Mazzoleni S, Wang E, Sovena G, Clavenna D, Franzin A, et al. Immunobiological characterization of cancer stem cells isolated from glioblastoma patients. Clin Cancer Res. 2010;16:800–13.

    Article  Google Scholar 

  6. Brown SD, Holt RA. Neoantigen characteristics in the context of the complete predicted MHC class I self-immunopeptidome. Oncoimmunology. 2018;8:1556080.

    Article  Google Scholar 

  7. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351:1463–9.

    Article  CAS  Google Scholar 

  8. Jefferies WA, Kolaitis G, Gabathuler R. IFN-gamma-induced recognition of the antigen-processing variant CMT.64 by cytolytic T cells can be replaced by sequential addition of beta 2 microglobulin and antigenic peptides. J Immunol. 1993;151:2974–85.

    CAS  PubMed  Google Scholar 

  9. Gabathuler R, Reid G, Kolaitis G, Driscoll J, Jefferies WA. Comparison of cell lines deficient in antigen presentation reveals a functional role for TAP-1 alone in antigen processing. J Exp Med. 1994;180:1415–25.

    Article  CAS  Google Scholar 

  10. Cai L, Michelakos T, Deshpande V, Arora KS, Yamada T, Ting DT, et al. Role of tumor-associated macrophages in the clinical course of pancreatic neuroendocrine tumors (PanNETs). Clin Cancer Res. 2019;25:2644–55.

    Article  Google Scholar 

  11. Lou Y, Vitalis TZ, Basha G, Cai B, Chen SS, Choi KB, et al. Restoration of the expression of transporters associated with antigen processing in lung carcinoma increases tumor-specific immune responses and survival. Cancer Res. 2005;65:7926–33.

    Article  CAS  Google Scholar 

  12. Chang CC, Pirozzi G, Wen SH, Chung IH, Chiu BL, Errico S, et al. Multiple structural and epigenetic defects in the human leukocyte antigen class I antigen presentation pathway in a recurrent metastatic melanoma following immunotherapy. J Biol Chem. 2015;290:26562–75.

    Article  CAS  Google Scholar 

  13. Morrison BJ, Steel JC, Morris JC. Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer-initiating cells. BMC Cancer. 2018;18:469.

    Article  Google Scholar 

  14. Setiadi AF, Omilusik K, David MD, Seipp RP, Hartikainen J, Gopaul R, et al. Epigenetic enhancement of antigen processing and presentation promotes immune recognition of tumors. Cancer Res. 2008;68:9601–7.

    Article  CAS  Google Scholar 

  15. Woan KV, Sahakian E, Sotomayor EM, Seto E, Villagra A. Modulation of antigen-presenting cells by HDAC inhibitors: implications in autoimmunity and cancer. Immunol Cell Biol. 2012;90:55–65.

    Article  CAS  Google Scholar 

  16. Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Disco. 2014;13:673–91.

    Article  CAS  Google Scholar 

  17. Topper MJ, Vaz M, Chiappinelli KB, DeStefano Shields CE, Niknafs N, Yen RC, et al. Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung. Cancer Cell. 2017;171:1284–1300.

    CAS  Google Scholar 

  18. Setiadi AF, David MD, Seipp RP, Hartikainen JA, Gopaul R, Jefferies WA. Epigenetic control of the immune escape mechanisms in malignant carcinomas. Mol Cell Biol. 2007;27:7886–94.

    Article  CAS  Google Scholar 

  19. Versteeg R, Noordermeer IA, Krüse-Wolters M, Ruiter DJ, Schrier PI. c-myc down-regulates class I HLA expression in human melanomas. EMBO J. 1988;7:1023–9.

    Article  CAS  Google Scholar 

  20. Yang W, Yu H, Shen Y, Liu Y, Yang Z, Sun T. MiR-146b-5p overexpression attenuates stemness and radioresistance of glioma stem cells by targeting HuR/lincRNA-p21/β-catenin pathway. Oncotarget. 2016;7:41505–26.

    PubMed  PubMed Central  Google Scholar 

  21. Wong TS, Chen S, Zhang MJ, Chan JY, Gao W. Epstein-Barr virus-encoded microRNA BART7 downregulates major histocompatibilitycomplex class I chain-related peptide A and reduces the cytotoxicity of natural killer cells to nasopharyngeal carcinoma. Oncol Lett. 2018; 16:2887–92.

  22. Wang B, Niu D, Lai L, Ren EC. p53 increases MHC class I expression by upregulating the endoplasmic reticulum aminopeptidase ERAP1. Nat Commun. 2013;4:2359.

    Article  Google Scholar 

  23. Zhu K, Wang J, Zhu J, Jiang J, Shou J, Chen X. p53 induces TAP1 and enhances the transport of MHC class I peptides. Oncogene. 1999;18:7740–7.

    Article  CAS  Google Scholar 

  24. Szatmári T, Lumniczky K, Désaknai S, Trajcevski S, Hídvégi EJ, Hamada H, et al. Detailed characterization of the mouse glioma 261 tumor model experimental glioblastomatherapy. Cancer Sci. 2006;97:546–53.

    Article  Google Scholar 

  25. Yang W, Liu Y, Gao R, Yu H, Sun T. HDAC6 inhibition induces glioma stem cells differentiation and enhances cellular radiation sensitivity through the SHH/Gli1 signaling pathway. Cancer Lett. 2018;415:164–76.

    Article  CAS  Google Scholar 

  26. Carugo A, Minelli R, Sapio L, Soeung M, Carbone F, Robinson FS, et al. p53 is a master regulator of proteostasis in SMARCB1-deficient malignant rhabdoid tumors. Cancer Cell. 2019;35:204–20.

    Article  CAS  Google Scholar 

  27. Durgeau A, Virk Y, Corgnac S, Mami-Chouaib F. Recent advances in targeting cd8 T-cell immunity for more effective cancer immunotherapy. Front Immunol. 2018;9:14.

    Article  Google Scholar 

  28. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005;353:2654–66.

    Article  CAS  Google Scholar 

  29. Lou Y, Seipp RP, Cai B, Chen SS, Vitalis TZ, Choi KB, et al. Tumour immunity and T cell memory are induced by low dose inoculation with a non-replicating adenovirus encoding TAP1. Vaccine. 2007;25:2331–9.

    Article  CAS  Google Scholar 

  30. Finocchiaro G, Pellegatta S. Immunotherapy with dendritic cells loaded with glioblastoma stem cells: from preclinical to clinical studies. Cancer Immunol Immunother. 2016;65:101–9.

    Article  CAS  Google Scholar 

  31. Vik-Mo EO, Nyakas M, Mikkelsen BV, Moe MC, Due-Tønnesen P, Suso EM, et al. Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma. Cancer Immunol Immunother. 2013;62:1499–509.

    Article  CAS  Google Scholar 

  32. Sun T, Wu H, Li Y, Huang Y, Yao L, Chen X, et al. Targeting transferrin receptor delivery of temozolomide for a potential glioma stem cell-mediated therapy. Oncotarget. 2017;8:74451–65.

    PubMed  PubMed Central  Google Scholar 

  33. Sadahiro H, Yoshikawa K, Ideguchi M, Kajiwara K, Ishii A, Ikeda E, et al. Pathological features of highly invasive glioma stem cells in a mouse xenograft model. Brain Tumor Pathol. 2014;31:77–84.

    Article  Google Scholar 

  34. Yang W, Wei J, Guo T, Shen Y, Liu F. Knockdown of miR-210 decreases hypoxic glioma stem cells stemness and radioresistance. Exp Cell Res. 2014;326:22–35.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81874080, 31870844, 31570851) and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Authors and Affiliations

  1. State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, 215123, Suzhou, Jiangsu, China

    Wei Yang, Ruoling Gao & Zenghe Xiu

  2. Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 215006, Suzhou, Jiangsu, China

    Yanyan Li & Ting Sun

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  1. Wei Yang
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Correspondence to Wei Yang or Ting Sun.

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Yang, W., Li, Y., Gao, R. et al. MHC class I dysfunction of glioma stem cells escapes from CTL-mediated immune response via activation of Wnt/β-catenin signaling pathway. Oncogene 39, 1098–1111 (2020). https://doi.org/10.1038/s41388-019-1045-6

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