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IGFBP2 promotes immunosuppression associated with its mesenchymal induction and FcγRIIB phosphorylation in glioblastoma


Autoři: Yunmian Liu aff001;  Chunyan Song aff001;  Faping Shen aff001;  Jing Zhang aff002;  Sonya Wei Song aff001
Působiště autorů: Center for Brain Disorders Research, Capital Medical University, Beijing Institute for Brain Disorders, Beijing Neurosurgical Institute, Beijing, People's Republic of China aff001;  Institute for Cancer Genetics, Irving Cancer Research Center, Columbia University, New York, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0222999

Souhrn

Immunotherapy shows a promise for treating glioblastoma (GBM), the most malignant and immunosuppressive glioma. The mesenchymal phenotype of cancer cells was frequently reported to be associated with their induction of immunosuppression within the cancer microenvironment. Overexpressed insulin-like growth factor binding protein 2 (IGFBP2) promotes GBM cell migration and invasion, and contributes to glioma progression and cancer recurrence and poor survival in GBM. However, whether IGFBP2 can induce immunosuppression in GBM was not reported yet. Thus, the study applied a syngeneic mouse GBM model, human GBM samples, and cancer-immune cell co-culture experiments to investigate the effect of IGFBP2 on GBM exposed immune cells and its association with the mesenchymal induction. We found that IGFBP2 promoted the mesenchymal feature of GBM cells. The inhibition of IGFBP2 relieved immunosuppression by increasing CD8+ T and CD19+ B cells and decreasing CD163+ M2 macrophages. Further, the IGFBP2-promoted immunosuppression was associated with its induction of the mesenchymal feature of GBM cells and the inhibitory phosphorylated FcγRIIB of GBM exposed immune cells. Blocking IGFBP2 suppressed tumor growth and improved survival of tumor bearing mice in the mouse GBM model. These findings support the notion that targeting the IGFBP2 may present an effective immunotherapeutic strategy for mesenchymal GBMs.

Klíčová slova:

B cells – Cancer treatment – Immune cells – Immune suppression – Immunohistochemistry techniques – Macrophages – Phosphorylation – Glioma


Zdroje

1. Nduom EK, Weller M, Heimberger AB. Immunosuppressive mechanisms in glioblastoma. Neuro Oncol. 2015;17 Suppl 7:vii9–vii14. Epub 2015/10/31. doi: 10.1093/neuonc/nov151 26516226; PubMed Central PMCID: PMC4625890.

2. Yang I, Tihan T, Han SJ, Wrensch MR, Wiencke J, Sughrue ME, et al. CD8+ T-cell infiltrate in newly diagnosed glioblastoma is associated with long-term survival. J Clin Neurosci. 2010;17(11):1381–5. Epub 2010/08/24. doi: 10.1016/j.jocn.2010.03.031 20727764; PubMed Central PMCID: PMC3064460.

3. Donson AM, Birks DK, Schittone SA, Kleinschmidt-DeMasters BK, Sun DY, Hemenway MF, et al. Increased immune gene expression and immune cell infiltration in high-grade astrocytoma distinguish long-term from short-term survivors. J Immunol. 2012;189(4):1920–7. Epub 2012/07/18. doi: 10.4049/jimmunol.1103373 22802421; PubMed Central PMCID: PMC3411857.

4. Dongre A, Rashidian M, Reinhardt F, Bagnato A, Keckesova Z, Ploegh HL, et al. Epithelial-to-Mesenchymal Transition Contributes to Immunosuppression in Breast Carcinomas. Cancer Res. 2017;77(15):3982–9. Epub 2017/04/22. doi: 10.1158/0008-5472.CAN-16-3292 28428275; PubMed Central PMCID: PMC5541771.

5. Ivliev AE, t Hoen PA, Sergeeva MG. Coexpression network analysis identifies transcriptional modules related to proastrocytic differentiation and sprouty signaling in glioma. Cancer Res. 2010;70(24):10060–70. Epub 2010/12/17. doi: 10.1158/0008-5472.CAN-10-2465 21159630.

6. Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 2005;436(7047):123–7. Epub 2005/07/08. doi: 10.1038/nature03688 16001073; PubMed Central PMCID: PMC2784913.

7. Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED, et al. Epithelial—mesenchymal and mesenchymal—epithelial transitions in carcinoma progression. J Cell Physiol. 2007;213(2):374–83. Epub 2007/08/08. doi: 10.1002/jcp.21223 17680632.

8. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9(3):157–73. Epub 2006/03/15. doi: 10.1016/j.ccr.2006.02.019 16530701.

9. Doucette T, Rao G, Rao A, Shen L, Aldape K, Wei J, et al. Immune heterogeneity of glioblastoma subtypes: extrapolation from the cancer genome atlas. Cancer Immunol Res. 2013;1(2):112–22. Epub 2014/01/11. doi: 10.1158/2326-6066.CIR-13-0028 24409449; PubMed Central PMCID: PMC3881271.

10. Prins RM, Soto H, Konkankit V, Odesa SK, Eskin A, Yong WH, et al. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res. 2011;17(6):1603–15. Epub 2010/12/08. doi: 10.1158/1078-0432.CCR-10-2563 21135147; PubMed Central PMCID: PMC3071163.

11. Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol. 2008;8(1):34–47. doi: 10.1038/nri2206 18064051.

12. Yan J, Kong LY, Hu J, Gabrusiewicz K, Dibra D, Xia X, et al. FGL2 as a Multimodality Regulator of Tumor-Mediated Immune Suppression and Therapeutic Target in Gliomas. Journal of the National Cancer Institute. 2015;107(8). doi: 10.1093/jnci/djv137 25971300; PubMed Central PMCID: PMC4554195.

13. Zhang C, Li J, Wang H, Song SW. Identification of a five B cell-associated gene prognostic and predictive signature for advanced glioma patients harboring immunosuppressive subtype preference. Oncotarget. 2016;7(45):73971–83. Epub 2016/10/16. doi: 10.18632/oncotarget.12605 27738332; PubMed Central PMCID: PMC5342028.

14. Song SW, Fuller GN, Khan A, Kong S, Shen W, Taylor E, et al. IIp45, an insulin-like growth factor binding protein 2 (IGFBP-2) binding protein, antagonizes IGFBP-2 stimulation of glioma cell invasion. Proc Natl Acad Sci U S A. 2003;100(24):13970–5. doi: 10.1073/pnas.2332186100 14617774; PubMed Central PMCID: PMC283530.

15. Wang GK, Hu L, Fuller GN, Zhang W. An interaction between insulin-like growth factor-binding protein 2 (IGFBP2) and integrin alpha5 is essential for IGFBP2-induced cell mobility. J Biol Chem. 2006;281(20):14085–91. Epub 2006/03/30. doi: 10.1074/jbc.M513686200 16569642.

16. Dunlap SM, Celestino J, Wang H, Jiang R, Holland EC, Fuller GN, et al. Insulin-like growth factor binding protein 2 promotes glioma development and progression. Proc Natl Acad Sci U S A. 2007;104(28):11736–41. doi: 10.1073/pnas.0703145104 17606927; PubMed Central PMCID: PMC1913900.

17. Das SK, Bhutia SK, Azab B, Kegelman TP, Peachy L, Santhekadur PK, et al. MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma. Cancer Res. 2013;73(2):844–54. doi: 10.1158/0008-5472.CAN-12-1681 23233738; PubMed Central PMCID: PMC3548987.

18. Gao S, Sun Y, Zhang X, Hu L, Liu Y, Chua CY, et al. IGFBP2 Activates the NF-kappaB Pathway to Drive Epithelial- Mesenchymal Transition and Invasive Character in Pancreatic Ductal Adenocarcinoma. Cancer Res. 2016;76(22):6543–54. Epub 2016/11/05. doi: 10.1158/0008-5472.CAN-16-0438 27659045; PubMed Central PMCID: PMC5315491.

19. Chua CY, Liu Y, Granberg KJ, Hu L, Haapasalo H, Annala MJ, et al. IGFBP2 potentiates nuclear EGFR-STAT3 signaling. Oncogene. 2016;35(6):738–47. Epub 2015/04/22. doi: 10.1038/onc.2015.131 25893308; PubMed Central PMCID: PMC4615268.

20. Azar WJ, Azar SH, Higgins S, Hu JF, Hoffman AR, Newgreen DF, et al. IGFBP-2 enhances VEGF gene promoter activity and consequent promotion of angiogenesis by neuroblastoma cells. Endocrinology. 2011;152(9):3332–42. Epub 2011/07/14. doi: 10.1210/en.2011-1121 21750048.

21. Phillips LM, Zhou X, Cogdell DE, Chua CY, Huisinga A, K RH, et al. Glioma progression is mediated by an addiction to aberrant IGFBP2 expression and can be blocked using anti-IGFBP2 strategies. J Pathol. 2016;239(3):355–64. Epub 2016/04/30. doi: 10.1002/path.4734 27125842; PubMed Central PMCID: PMC4915980.

22. Preza GC, Yang OO, Elliott J, Anton PA, Ochoa MT. T lymphocyte density and distribution in human colorectal mucosa, and inefficiency of current cell isolation protocols. PLoS One. 2015;10(4):e0122723. Epub 2015/04/10. doi: 10.1371/journal.pone.0122723 25856343; PubMed Central PMCID: PMC4391713.

23. LaFrance-Corey RG, Howe CL. Isolation of brain-infiltrating leukocytes. J Vis Exp. 2011(52). Epub 2011/06/23. doi: 10.3791/2747 21694694; PubMed Central PMCID: PMC3178654.

24. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110. Epub 2010/02/05. doi: 10.1016/j.ccr.2009.12.020 20129251; PubMed Central PMCID: PMC2818769.

25. Bhat KP, Salazar KL, Balasubramaniyan V, Wani K, Heathcock L, Hollingsworth F, et al. The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev. 2011;25(24):2594–609. Epub 2011/12/23. doi: 10.1101/gad.176800.111 22190458; PubMed Central PMCID: PMC3248681.

26. Bhat KPL, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, et al. Mesenchymal differentiation mediated by NF-kappaB promotes radiation resistance in glioblastoma. Cancer Cell. 2013;24(3):331–46. Epub 2013/09/03. doi: 10.1016/j.ccr.2013.08.001 23993863; PubMed Central PMCID: PMC3817560.

27. Komohara Y, Ohnishi K, Kuratsu J, Takeya M. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol. 2008;216(1):15–24. Epub 2008/06/17. doi: 10.1002/path.2370 18553315.

28. Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci. 2016;19(1):20–7. doi: 10.1038/nn.4185 26713745; PubMed Central PMCID: PMC4876023.

29. Ishiura N, Nakashima H, Watanabe R, Kuwano Y, Adachi T, Takahashi Y, et al. Differential phosphorylation of functional tyrosines in CD19 modulates B-lymphocyte activation. Eur J Immunol. 2010;40(4):1192–204. doi: 10.1002/eji.200939848 20101619.

30. Kalli KR, Krco CJ, Hartmann LC, Goodman K, Maurer MJ, Yu C, et al. An HLA-DR-degenerate epitope pool detects insulin-like growth factor binding protein 2-specific immunity in patients with cancer. Cancer Res. 2008;68(12):4893–901. doi: 10.1158/0008-5472.CAN-07-6726 18559537; PubMed Central PMCID: PMC2744636.

31. Park KH, Gad E, Goodell V, Dang Y, Wild T, Higgins D, et al. Insulin-like growth factor-binding protein-2 is a target for the immunomodulation of breast cancer. Cancer Res. 2008;68(20):8400–9. doi: 10.1158/0008-5472.CAN-07-5891 18922913; PubMed Central PMCID: PMC2596961.

32. Cecil DL, Holt GE, Park KH, Gad E, Rastetter L, Childs J, et al. Elimination of IL-10-inducing T-helper epitopes from an IGFBP-2 vaccine ensures potent antitumor activity. Cancer Res. 2014;74(10):2710–8. Epub 2014/04/30. doi: 10.1158/0008-5472.CAN-13-3286 24778415; PubMed Central PMCID: PMC4037234.

33. Shen F, Song C, Liu Y, Zhang J, Wei Song S. IGFBP2 Promotes Neural Stem Cell Maintenance and Proliferation Differentially Associated with Glioblastoma Subtypes. Brain Res. 2018. Epub 2018/10/23. doi: 10.1016/j.brainres.2018.10.018 30347220.

34. Ladanyi A, Kiss J, Mohos A, Somlai B, Liszkay G, Gilde K, et al. Prognostic impact of B-cell density in cutaneous melanoma. Cancer Immunol Immunother. 2011;60(12):1729–38. doi: 10.1007/s00262-011-1071-x 21779876.

35. Nielsen JS, Sahota RA, Milne K, Kost SE, Nesslinger NJ, Watson PH, et al. CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin Cancer Res. 2012;18(12):3281–92. doi: 10.1158/1078-0432.CCR-12-0234 22553348.

36. Germain C, Gnjatic S, Tamzalit F, Knockaert S, Remark R, Goc J, et al. Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer. Am J Respir Crit Care Med. 2014;189(7):832–44. doi: 10.1164/rccm.201309-1611OC 24484236.

37. Hennequin A, Derangere V, Boidot R, Apetoh L, Vincent J, Orry D, et al. Tumor infiltration by Tbet+ effector T cells and CD20+ B cells is associated with survival in gastric cancer patients. Oncoimmunology. 2016;5(2):e1054598. doi: 10.1080/2162402X.2015.1054598 27057426; PubMed Central PMCID: PMC4801425.

38. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000;6(4):443–6. Epub 2000/03/31. doi: 10.1038/74704 10742152.


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