Skip to main content

Advertisement

Log in

The novel immunotherapeutic molecule T11TS modulates glioma-induced changes of key components of the immunological synapse in favor of T cell activation and glioma abrogation

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

T-cell-mediated immune responses are typically low in conditions of malignant glioma which has been known to cause marked immunesuppression and dysregulate major T-cell signaling molecules. Thus, T-cell-based immunotherapies are currently in vogue in the treatment of malignant glioma. The novel glycopeptide, T11TS/S-LFA-3/S-CD58 has previously been shown by our group to be highly efficacious in glioma abrogation in in vivo and in vitro conditions. This glycopeptide ligands to the costimulatory CD2 molecule on T-cells, causing profound immune stimulation leading to glioma abrogation, suggesting probable involvement of T11TS in modulation of the T-cell signaling pathway. The present study offers a multi-targeted approach towards repair of some of the key components of the immunological synapse at the T-cell-APC interface and is therefore the first of its kind to offer a holistic model of restoration of immunological synapse components so as to trigger T-cells towards activation against glioma. The study thus indicates that the totally dysregulated molecular events at the immunological synapse in glioma are restored back to normal levels with the administration of T11TS, which finally culminates in glioma abrogation. The present study thus delineates an important T-cell signaling approach whereby T11TS acts as an anti-neoplastic agent, thus helping to chart out newer avenues in the fight against gliomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Rolle CE, Sengupta S, Lesniak MS (2012) Mechanisms of immune evasion by gliomas. Adv Exp Med Biol 746:53–76

    Article  PubMed  CAS  Google Scholar 

  2. Finke J, Ferrone S, Frey A, Mufson A, Ochoa A (1999) Where have all the T cells gone? Mechanisms of immune evasion by tumors. Immunol Today 20(4):158–160

    Article  PubMed  CAS  Google Scholar 

  3. Elliott LH, Brooks WH, Roszman TL (1984) Cytokinetic basis for the impaired activation of lymphocytes from patients with primary intracranial tumors. J Immunol 132(3):1208–1215

    PubMed  CAS  Google Scholar 

  4. Ahmed N, Salsman VS, Kew Y, Shaffer D, Powell S, Zhang YJ, Grossman GR, Heslop HE, Gottschalk S (2010) HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin Cancer Res 16(2):474–485

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Eshhar Z (1997) Tumor-specific T-bodies: towards clinical application. Cancer Immunol Immunother 45(3–4):131–136

    Article  PubMed  CAS  Google Scholar 

  6. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJM, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Hünig T, Tiefenthaler G, Mitnacht R, Köhler C, Lottspeich F, Meuer S (1987) The “erythrocyte receptor” of T-lymphocytes and T11 target structure (T11TS): complementary cell interaction molecules involved in T-cell activation. Behring Inst Mitt 81:31–40

    PubMed  Google Scholar 

  8. Fox DA, Hussey RE, Fitzgerald KA, Bensussan A, Daley JF, Schlossman SF, Reinherz EL (1985) Activation of human thymocytes via the 50KD T11 sheep erythrocyte binding protein induces the expression of interleukin 2 receptors on both T3 + and T3- populations. J Immunol 134(1):330–335

    PubMed  CAS  Google Scholar 

  9. Sarkar S, Begum Z, Dutta S, Dutta SK, Chaudhuri S, Chaudhuri S (2002) Sheep form of leucocyte function antigen-3 (T11TS) exerts immunostimulatory and anti-tumor activity against experimental brain tumor. A new approach to biological response modifier therapy. J Exp Clin Cancer Res 21(1):95–106

    PubMed  CAS  Google Scholar 

  10. Sarkar S, Ghosh A, Mukherjee J, Chaudhuri S, Chaudhuri S (2004) CD2-SLFA3/T11TS interaction facilitates immune activation and glioma regression by apoptosis. Cancer Biol Ther 3(11):1121–1128

    Article  PubMed  CAS  Google Scholar 

  11. Mukherjee J, Sarkar S, Ghosh A, Duttagupta AK, Chaudhuri S, Chaudhuri S (2004) Immunotherapeutic effects of T11TS/S-LFA3 against nitrosocompound mediated neural genotoxicity. Toxicol Lett 150(3):239–257

    Article  PubMed  CAS  Google Scholar 

  12. Sarkar P, Bhattacharjee M, Acharya S, Ghosh A, Tripathi SK, Chaudhuri S (2007) Acute toxicity studies of T11TS: a glycopeptide with antineoplastic effects against glioma. Toxicol Int 14:47–56

    CAS  Google Scholar 

  13. Sarkar P, Bhattacharjee M, Acharya S, Das Gupta S, Guha D, Sandhu M, Chaudhuri S (2010) Subacute toxicity study of T11TS, a novel glycopeptide against glioma. Adv Pharmacol Toxicol 11:1–10

    CAS  Google Scholar 

  14. Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML (1999) The immunological synapse: a molecular machine controlling T cell activation. Science 285:221–227

    Article  PubMed  CAS  Google Scholar 

  15. Vĕtvicka V, Fornůsek L, Tlaskalová H (1981) Comparison of different methods for separation of human, mouse and rat macrophages and lymphocytes. Folia Biol (Praha) 27(3):194–202

    Google Scholar 

  16. Bhattacharya D, Singh MK, Chaudhuri S, Basu AK, Chaudhuri S (2013) T11TS impedes glioma angiogenesis by inhibiting VEGF signaling and pro-survival PI3 K/Akt/eNOS pathway with concomitant upregulation of PTEN in brain endothelial cells. J Neurooncol 113(1):13–25

    Article  PubMed  CAS  Google Scholar 

  17. Gruber IV, El Yousfi S, Dürr-Störzer S, Wallwiener D, Solomayer EF, Fehm T (2008) Down-regulation of CD28, TCR-zeta (ζ) and up-regulation of FAS in peripheral cytotoxic T-cells of primary breast cancer patients. Anticancer Res 28(2A):779–784

    PubMed  CAS  Google Scholar 

  18. Clevers H, Alarcon B, Wileman T, Terhost C (1988) The T cell receptor/CD3 complex: a dynamic protein ensemble. Ann Rev Immunol 6:629–662

    Article  CAS  Google Scholar 

  19. Kono K, Salazar-Onfray F, Petersson M, Hansson J, Masucci G, Wasserman K, Nakazawa T, Anderson P, Kiessling R (1996) Hydrogen peroxide secreted by tumor-derived macrophages downmodulates signal-transducing zeta molecules and inhibits tumor-specific T cell- and natural killer cell-mediated cytotoxicity. Eur J Immunol 26(6):1308–1313

    Article  PubMed  CAS  Google Scholar 

  20. Chang YC, Chen TC, Lee CT, Yang CY, Wang HW, Wang CC, Hsieh SL (2008) Epigenetic control of MHC class II expression in tumor-associated macrophages by decoy receptor 3. Blood 111(10):5054–5063

    Article  PubMed  CAS  Google Scholar 

  21. Hahn WC, Burakoff SJ, Bierer BE (1993) Signal transduction pathways involved in T cell receptor-induced regulation of CD2 avidity for CD58. J Immunol 150(7):2607–2619

    PubMed  CAS  Google Scholar 

  22. Thomas RM, Gao L, Wells AD (2005) Signals from CD28 induce stable epigenetic modification of the IL-2 promoter. J Immunol 174(8):4639–4646

    Article  PubMed  CAS  Google Scholar 

  23. Siu E, Carreno BM, Madrenas J (2003) TCR subunit specificity of CTLA-4-mediated signaling. J Leukoc Biol 74(6):1102–1107

    Article  PubMed  CAS  Google Scholar 

  24. McAdam AJ, Schweitzer AN, Sharpe AH (1998) The role of B7 costimulation in activation and differentiation of CD4 + and CD8 + T cells. Immunol Rev 165:231–247

    Article  PubMed  CAS  Google Scholar 

  25. Chaudhuri S, Ghosh A (2006) Glioma therapy: a novel insight in the immunotherapeutic regime with T11TS/SLFA-3. CNS Agents in Medic Chem 6(4):245–270

    CAS  Google Scholar 

  26. Agarwal SG, Marquet J, Plumas J, Rouard H, Delfau-Larue MH, Gaulard P, Boumsell L, Reyes F, Bensussan A, Farcet JP (2000) Multiple co-stimulatory signals are required for triggering proliferation of T cells from human secondary lymphoid tissue. Int Immunol 13(4):441–450

    Article  Google Scholar 

  27. Lal G, Shaila MS, Nayak R (2006) Activated mouse T cells downregulate, process and present their surface TCR to cognate anti-idiotypic CD4 + T cells. Immunol Cell Biol 84:145–153

    Article  PubMed  CAS  Google Scholar 

  28. Ahmadi M, King JW, Xue S, Voisine C, Holler A, Wright GP, Waxman J, Morris E, Stauss HJ (2011) CD3 limits the efficacy of TCR gene therapy in vivo. Blood 118(13):3528–3537

    Article  PubMed  CAS  Google Scholar 

  29. Baker BM, Scott DR, Blevins SJ, Hawse WF (2012) Structural and dynamic control of T-cell receptor specificity, cross-reactivity and binding mechanism. Immunol Rev 250(1):10–31

    Article  PubMed  Google Scholar 

  30. Muraille E, Andris F, Pajak B, Wissing KM, De Smedt F, Desalle T, Goldman M, Alegre M, Urbain J, Moser M, Leo O (1999) Downregulation of antigen-presenting cell functions after administration of mitogenic anti-CD3 monoclonal antibodies in mice. Blood 94(12):4347–4357

    PubMed  CAS  Google Scholar 

  31. Morford LA, Elliott LH, Carlson SL, Brooks WH, Roszman TL (1997) T cell receptor-mediated signaling is defective in T cells obtained from patients with primary intracranial tumors. J Immunol 159(9):4415–4425

    PubMed  CAS  Google Scholar 

  32. Shores EW, Tran T, Grinberg A, Sommers CL, Shen H, Love PE (1997) Role of the multiple T cell receptor (TCR)-z chain signaling motifs in selection of the T cell repertoire. J Exp Med 185(5):893–900

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Renner C, Ohnesorge S, Held G, Bauer S, Jung W, Pfitzenmeier JP, Pfreundschuh M (1996) T cells from patients with Hodgkin’s disease have a defective T cell receptor ζ chain expression that is reversible by T-cell stimulation with CD3 and CD28. Blood 88(1):236–241

    PubMed  CAS  Google Scholar 

  34. Salvadori S, Gansbacher B, Zier K (1994) Functional defects are associated with abnormal signal transduction in T cells of mice inoculated with parental but not IL-2 secreting tumor cells. Cancer Gene Ther 1(3):165–170

    PubMed  CAS  Google Scholar 

  35. Lee S, Margolin K (2011) Cytokines in cancer immunotherapy. Cancers 3(4):3856–3893

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Ghosh A, Mukherjee J, Bhattacharjee M, Sarkar P, Acharya S, Chaudhuri S, Chaudhuri S (2007) The other side of the coin: beneficiary effect of ‘oxidative burst’ upsurge with T11TS facilitates the elimination of glioma cells. Cell Mol Biol 53(5):53–62

    PubMed  CAS  Google Scholar 

  37. June CH, Ledbetter JA, Linsey PS, Thompson CB (1990) Role of the CD28 receptor in T-cell activation. Immunol Today 11(6):211–216

    Article  PubMed  CAS  Google Scholar 

  38. Berg M, Zavazava N (2008) Regulation of CD28 expression on CD8 + T cells by CTLA-4. J Leukoc Biol 83(4):853–863

    Article  PubMed  CAS  Google Scholar 

  39. Walunas TL, Bakker CY, Bluestone JA (1996) CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med 183(6):2541–2550

    Article  PubMed  CAS  Google Scholar 

  40. Michel F, Attal-Bonnefoy G, Mangino G, Mise-Omata S, Acuto O (2001) CD28 as a molecular amplifier extending TCR ligation and signaling capabilities. Immunity 15(16):935–945

    Article  PubMed  CAS  Google Scholar 

  41. Koyasu S (2003) The role of PI3 K in immune cells. Nat Immunol 4(4):313–319

    Article  PubMed  CAS  Google Scholar 

  42. Agarwalla P, Barnard Z, Fecci P, Dranoff G, Curry WT Jr (2012) Sequential immunotherapy by vaccination with GM-CSF-expressing glioma cells and CTLA-4 blockade effectively treats established murine intracranial tumors. J Immunother 35(5):385–389

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  43. Alberola-Ila J, Places L, de la Calle O, Romero M, Yagüe J, Gallart T, Vives J, Lozano F (1991) Stimulation through the TCR/CD3 complex up-regulates the CD2 surface expression on human T lymphocytes. J Immunol 146(4):1085–1092

    PubMed  CAS  Google Scholar 

  44. Koyasu S, Lawton T, Novick D, Recny MA, Siliciano RF, Wallner BP, Reinherz EL (1990) Role of interaction of CD2 molecules with lymphocyte function-associated antigen 3 in T cell recognition of normal antigen. Proc Natl Acad Sci USA 87(7):2603–2607

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  45. Crawford K, Stark A, Kitchens B, Sternheim K, Pantazopoulos V, Triantafellow E, Wang Z, Vasir B, Larsen CE, Gabuzda D, Reinherz E, Alper CA (2003) CD2 engagement induces dendritic cell activation: implications for immune surveillance and T-cell activation. Blood 102(5):1745–1752

    Article  PubMed  CAS  Google Scholar 

  46. Kaizuka Y, Douglass AD, Vardhana S, Dustin ML, Vale RD (2009) The coreceptor CD2 uses plasma membrane microdomains to transduce signals in T cells. J Cell Biol 185(3):521–534

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Ghosh A, Bhattacharya M, Sarkar P, Acharya S, Chaudhuri S (2010) T11 target structure exerts effector function by activating immune cells in CNS against glioma where cytokine modulation provides a favourable microenvironment. Ind J Exp Biol 48:879–888

    CAS  Google Scholar 

  48. Kumar P, Acharya S, Chatterjee S, Kumari A, Chaudhuri S, Singh MK, Ghosh SN, Chaudhuri S (2012) Immunomodulatory role of T11TS in respect to cytotoxic lymphocytes in four grades of human glioma. Cell Immunol 276(1–2):176–186

    Article  PubMed  CAS  Google Scholar 

  49. Chen X, Woiciechowsky A, Raffegerst S, Schendel D, Kolb H, Roskrow M (2000) Impaired expression of the CD3-zeta chain in peripheral blood T cells of patients with chronic myeloid leukaemia results in an increased susceptibility to apoptosis. Brit J Haematol 111(3):817–825

    CAS  Google Scholar 

  50. Gorelik L, Flavell RA (2000) Abrogation of TGFβ signalling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12(2):171–181

    Article  PubMed  CAS  Google Scholar 

  51. Wingren AG, Dahlenborg K, Björklund M, Hedlund G, Kalland T, Sjögren HO, Ljungdahl A, Olsson T, Ekre HP, Sansom D (1993) Monocyte-regulated IFN-gamma production in human T cells involves CD2 signaling. J Immunol 151(3):1328–1336

    PubMed  CAS  Google Scholar 

  52. Akdis CA, Joss A, Akdis M, Faith A, Blaser K (2000) A molecular basis for T cell suppression by IL-10: cD28-associated IL-10 receptor inhibits CD28 tyrosine phosphorylation and phosphatidylinositol 3-kinase binding. FASEB J 14(12):1666–1668

    PubMed  CAS  Google Scholar 

  53. Chen W, Jin W, Wahl SM (1998) Engagement of cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) induces transforming growth factor β (TGF-β) production by murine CD4 + T cells. J Exp Med 188(10):1849–1857

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  54. Akbasak A, Oldfield EH, Saris SC (1991) Expression and modulation of major histocompatibility antigens on murine primary brain tumor in vitro. J Neurosurg 75(6):922–929

    Article  PubMed  CAS  Google Scholar 

  55. Pechhold K, Patterson NB, Craighead N, Lee KP, June CH, Harlan DM (1997) Inflammatory cytokines IFN-gamma plus TNF-alpha induce regulated expression of CD80 (B7-1) but not CD86 (B7-2) on murine fibroblasts. J Immunol 158(10):4921–4929

    PubMed  CAS  Google Scholar 

  56. Huang L, Crispe IN (1993) Superantigen-driven peripheral deletion of T cells. Apoptosis occurs in cells that have lost the alpha/beta T cell receptor. J Immunol 151(4):1844–1851

    PubMed  CAS  Google Scholar 

  57. Reichert TE, Rabinowich H, Johnson JT, Whiteside TL (1998) Mechanisms responsible for signaling and functional defects. J Immunother 21(4):295–306

    Article  PubMed  CAS  Google Scholar 

  58. Bhattacharjee M, Acharya S, Ghosh A, Sarkar P, Chatterjee S, Chaudhuri S, Kumar P (2008) Bax and Bid act in synergy to bring about T11TS mediated glioma apoptosis via the release of mitochondrial cytochrome c and subsequent caspase activation. Int Immunol 20(12):1489–1505

    Article  PubMed  CAS  Google Scholar 

  59. Ayroldi E, Migliorati G, Cannarile L, Moraca R, Delfino DV, Riccardi C (1997) CD2 rescues T cells from T-cell receptor/CD3 apoptosis: a role for the Fas/Fas-L system. Blood 89(10):3717–3726

    PubMed  CAS  Google Scholar 

  60. Mukherjee J, Ghosh A, Sarkar P, Mazumdar M, Banerjee C, Chaudhuri S (2005) Immunotherapy with T11TS/SLFA-3 specifically induces apoptosis of brain tumor cells by augmenting intracranial immune status. Anticancer Res 25:2905–2920

    PubMed  CAS  Google Scholar 

  61. Acharya S, Chatterjee S, Kumar P, Bhattacharjee M, Chaudhuri S, Chaudhuri S (2010) Induction of G1 arrest in glioma cells by T11TS is associated with up-regulation of Cip1/Kip1 and concurrent downregulation of cyclin D (1 & 3). Anticancer Drugs 21(1):53–64

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors are grateful to the Department of Science and Technology (DST), Govt. of India for funding this work.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Swapna Chaudhuri.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 11 kb)

Supplementary material 2 (TIFF 17341 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chaudhuri, S., Singh, M.K., Bhattacharya, D. et al. The novel immunotherapeutic molecule T11TS modulates glioma-induced changes of key components of the immunological synapse in favor of T cell activation and glioma abrogation. J Neurooncol 120, 19–31 (2014). https://doi.org/10.1007/s11060-014-1528-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-014-1528-9

Keywords

Navigation