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Rejection of RG-2 gliomas is mediated by microglia and T lymphocytes

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Summary

Immunotherapy holds great promise for the treatment of invasive brain tumors, and we are interested specifically in evaluating immune stimulation of microglial cells as one potential strategy. In order to better understand the tumor fighting capabilities of microglial cells, we have compared the responses of syngeneic (Fisher 344) and allogeneic (Wistar) rat strains after intracranial implantation of RG-2 gliomas. Animals were evaluated by clinical examination, magnetic resonance imaging (MRI) and immunohistochemistry for microglial and other immune cell antigens. While lethal RG-2 gliomas developed in all of the Fisher 344 rats, tumors grew variably in the Wistar strain, sometimes reaching considerable sizes, but eventually all of them regressed. Tumor regression was associated with greater numbers of T cells and CD8 positive cells and increases in MHC I and CD4 positive microglia. Our findings suggest that the combined mobilization of peripheral and CNS endogenous immune cells is required for eradicating large intracranial tumors.

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References

  1. Akman F, Cooper RA, Sen M, et al: Validation of the Medical Research Council and a newly developed prognostic index in patients with malignant glioma: how useful are prognostic indices in routine clinical practice? J Neurooncol 59: 39–47, 2002

    Article  PubMed  Google Scholar 

  2. 2.Basso U, Ermani M, Vastola F, et al: Non-cytotoxic therapies for malignant gliomas J Neurooncol 58: 57–69, 2002

    Article  PubMed  Google Scholar 

  3. Nieder C, Grosu AL, Molls M: A comparison of treatment results for recurrent malignant gliomas Cancer Treat Rev 26: 397–409, 2000

    Article  PubMed  CAS  Google Scholar 

  4. Greene HS The transplantation of tumors to the brains of heterologous species Cancer Res 11: 529–534, 1951

    PubMed  CAS  Google Scholar 

  5. Murphy JB, Sturm E Conditions determining the transplantability of tissues in the brain J Exp Med 38: 183–197, 1923

    Article  CAS  PubMed  Google Scholar 

  6. Shirai Y Transplantation of rat sarcoma in adult heterogeneous animals Japan Med World 1: 14–15, 1921

    Google Scholar 

  7. Tansley K The development of the rat eye in graft J Exp Biol 22: 221–223, 1946

    Google Scholar 

  8. Cserr HF, Knopf PM Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view Immunol Today 13: 507–512, 1992

    Article  PubMed  CAS  Google Scholar 

  9. Cserr HF, Harling-Berg CJ, Knopf PM Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance Brain Pathol 2: 269–276, 1992

    Article  PubMed  CAS  Google Scholar 

  10. Hickey WF, Hsu BL, Kimura H T-lymphocyte entry into the central nervous system J Neurosci Res 28: 254–260, 1991

    Article  PubMed  CAS  Google Scholar 

  11. Aloisi F, Ria F, Adorini L Regulation of T-cell responses by CNS antigen-presenting cells: different roles for microglia and astrocytes Immunol Today 21: 141–147, 2000

    Article  PubMed  CAS  Google Scholar 

  12. Aloisi F Immune function of microglia Glia 36: 165–179, 2001

    Article  PubMed  CAS  Google Scholar 

  13. Becher B, Prat A, Antel JP Brain-immune connection: immuno-regulatory properties of CNS-resident cells Glia 29: 293–304, 2000

    Article  PubMed  CAS  Google Scholar 

  14. Graeber MB, Scheithauer BW, Kreutzberg GW Microglia in brain tumors Glia 40: 252–259, 2002

    Article  PubMed  Google Scholar 

  15. Hickey WF, Kimura H Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo Science 239: 290–292, 1988

    Article  PubMed  CAS  Google Scholar 

  16. Ford AL, Goodsall AL, Hickey WF, et al: Normal adult ramified microglia separated from other central nervous system macrophages by flow cytometric sorting. Phenotypic differences defined and direct ex vivo antigen presentation to myelin basic protein-reactive CD4+ T cells compared J Immunol 154: 4309–4321, 1995

    PubMed  CAS  Google Scholar 

  17. Barth RF Rat brain tumor models in experimental neuro-oncology: the 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 gliomas J Neurooncol 36: 91–102, 1998

    Article  PubMed  CAS  Google Scholar 

  18. Tzeng JJ, Barth RF, Orosz CG, et al: Phenotype and functional activity of tumor-infiltrating lymphocytes isolated from immunogenic and nonimmunogenic rat brain tumors Cancer Res 51: 2373–2378, 1991

    PubMed  CAS  Google Scholar 

  19. Parsa AT, Chakrabarti I, Hurley PT, et al: Limitations of the C6/Wistar rat intracerebral glioma model: implications for evaluating immunotherapy Neurosurgery 47: 993–999, 2000 discussion 999–1000

    Article  PubMed  CAS  Google Scholar 

  20. Ko L, Koestner A, Wechsler W Characterization of cell cycle and biological parameters of transplantable glioma cell lines and clones Acta Neuropathol (Berl) 51: 107–111, 1980

    Article  CAS  Google Scholar 

  21. Stojiljkovic M, Piperski V, Dacevic M, et al: Characterization of 9L glioma model of the Wistar rat J Neurooncol 63: 1–7, 2003

    Article  PubMed  Google Scholar 

  22. Saini M, Bellinzona M, Meyer F, et al: Morphometrical characterization of two glioma models in the brain of immunocompetent and immunodeficient rats J Neurooncol 42: 59–67, 1999

    Article  PubMed  CAS  Google Scholar 

  23. Albright AL, Gill TJ III, Geyer SJ Immunogenetic control of brain tumor growth in rats Cancer Res 37: 2512–2521, 1977

    PubMed  CAS  Google Scholar 

  24. Lodin Z, Hasek M, Chutna J, et al: Transplantation immunity in the brain J Neurosci Res 3: 275–280, 1977

    Article  PubMed  CAS  Google Scholar 

  25. Scheinberg LC, Edelman FL, Levy WA Is the brain “an immunologically privileged site”? I. Studies based on intracerebral tumor homotransplantation and isotransplantation to sensitized hosts Arch Neurol 11: 248–264, 1964

    PubMed  CAS  Google Scholar 

  26. Scheinberg LC, Levy A, Edelman F Is the brain an “immunologically privileged site”? 2. Studies in induced host resistance to transplantable mouse glioma following irradiation of prior implants Arch Neurol 13: 283–286, 1965

    PubMed  CAS  Google Scholar 

  27. Chrisman CL, Mariani CL, Platt SR, Clemmons RC: Neurology for the Small Animal Practitioner. Teton New Media, Jackson, 2003

  28. Hasek M, Chutna J, Sladecek M, et al: Immunological tolerance and tumor allografts in the brain Nature 268: 68–69, 1977

    Article  PubMed  CAS  Google Scholar 

  29. Medawar PB Immunity to homologous grafted skin. III. The fate of skin homografts transplanted to the brain, to subcutaneous tissue and to the anterior chamber of the eye Br J Exp Pathol 29: 58–69, 1948

    PubMed  CAS  Google Scholar 

  30. Brooks WH, Markesbery WR, Gupta GD, et al: Relationship of lymphocyte invasion and survival of brain tumor patients Ann Neurol 4: 219–224, 1978

    Article  PubMed  CAS  Google Scholar 

  31. Burger PC, Vogel FS, Green SB, et al: Glioblastoma multiforme and anaplastic astrocytoma. Pathologic criteria and prognostic implications Cancer 56: 1106–1111, 1985

    Article  PubMed  CAS  Google Scholar 

  32. Di Lorenzo N, Palma L, Nicole S Lymphocytic infiltration in long-survival glioblastomas: possible host’s resistance Acta Neurochir (Wien) 39: 27–33, 1977

    Article  CAS  Google Scholar 

  33. Palma L, Di Lorenzo N, Guidetti B Lymphocytic infiltrates in primary glioblastomas and recidivous gliomas. Incidence, fate, and relevance to prognosis in 228 operated cases J Neurosurg 49: 854–861, 1978

    Article  PubMed  CAS  Google Scholar 

  34. Kurts C Cross-presentation: inducing CD8 T cell immunity and tolerance J Mol Med. 78: 326–332, 2000

    Article  PubMed  CAS  Google Scholar 

  35. Okamoto Y, Yamashita J, Hasegawa M, et al: Cervical lymph nodes play the role of regional lymph nodes in brain tumour immunity in rats Neuropathol Appl Neurobiol 25: 113–122, 1999

    Article  PubMed  CAS  Google Scholar 

  36. Weller RO, Kida S, Zhang ET Pathways of fluid drainage from the brain-morphological aspects and immunological significance in rat and man Brain Pathol 2: 277–284, 1992

    Article  PubMed  CAS  Google Scholar 

  37. Aloisi F, Ria F, Columba-Cabezas S, et al: Relative efficiency of microglia, astrocytes, dendritic cells and B cells in naive CD4+ T cell priming and Th1/Th2 cell restimulation Eur J Immunol 29: 2705–2714, 1999

    Article  PubMed  CAS  Google Scholar 

  38. Flugel A, Labeur MS, Grasbon-Frodl EM, et al: Microglia only weakly present glioma antigen to cytotoxic T cells Int J Dev Neurosci 17: 547–556, 1999

    Article  PubMed  CAS  Google Scholar 

  39. Watters JJ, Schartner JM, Badie B Microglia function in brain tumors J Neurosci Res 81: 447–455, 2005

    Article  PubMed  CAS  Google Scholar 

  40. Kreutzberg GW Microglia: a sensor for pathological events in the CNS Trends Neurosci 19: 312–318, 1996

    Article  PubMed  CAS  Google Scholar 

  41. Perry VH A revised view of the central nervous system microenvironment and major histocompatibility complex class II antigen presentation J Neuroimmunol 90: 113–121, 1998

    Article  PubMed  CAS  Google Scholar 

  42. Heath WR, Carbone FR Cross-presentation, dendritic cells, tolerance and immunity Annu Rev Immunol 19: 47–64, 2001

    Article  PubMed  CAS  Google Scholar 

  43. Albert ML, Sauter B, Bhardwaj N Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs Nature 392: 86–89, 1998

    Article  PubMed  CAS  Google Scholar 

  44. Norbury CC, Chambers BJ, Prescott AR, et al: Constitutive macropinocytosis allows TAP-dependent major histocompatibility complex class I presentation of exogenous soluble antigen by bone marrow-derived dendritic cells Eur J Immunol 27: 280–288, 1997

    Article  PubMed  CAS  Google Scholar 

  45. Shen Z, Reznikoff G, Dranoff G, et al: Cloned dendritic cells can present exogenous antigens on both MHC class I and class II molecules J Immunol 158: 2723–2730, 1997

    PubMed  CAS  Google Scholar 

  46. Kovacsovics-Bankowski M, Clark K, Benacerraf B, et al: Efficient major histocompatibility complex class I presentation of exogenous antigen upon phagocytosis by macrophages Proc Natl Acad Sci USA90: 4942–4946, 1993

    Article  PubMed  CAS  Google Scholar 

  47. Norbury CC, Hewlett LJ, Prescott AR, et al: Class I MHC presentation of exogenous soluble antigen via macropinocytosis in bone marrow macrophages Immunity 3: 783–791, 1995

    Article  PubMed  CAS  Google Scholar 

  48. Arina A, Tirapu I, Alfaro C, et al: Clinical implications of antigen transfer mechanisms from malignant to dendritic cells exploiting cross-priming Exp Hematol 30: 1355–1364, 2002

    Article  PubMed  CAS  Google Scholar 

  49. Calzascia T, Di Berardino-Besson W, Wilmotte R, et al: Cutting edge: cross-presentation as a mechanism for efficient recruitment of tumor-specific CTL to the brain J Immunol 171: 2187–2191, 2003

    PubMed  CAS  Google Scholar 

  50. Huang AY, Golumbek P, Ahmadzadeh M, et al: Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens Science 264: 961–965, 1994

    Article  PubMed  CAS  Google Scholar 

  51. Okada H, Tsugawa T, Sato H, et al: Delivery of interferon-alpha transfected dendritic cells into central nervous system tumors enhances the antitumor efficacy of peripheral peptide-based vaccines Cancer Res 64: 5830–5838, 2004

    Article  PubMed  CAS  Google Scholar 

  52. Robinson BW, Lake RA, Nelson DJ, et al: Cross-presentation of tumour antigens: evaluation of threshold, duration, distribution and regulation Immunol Cell Biol 77: 552–558, 1999

    Article  PubMed  CAS  Google Scholar 

  53. Selenko N, Majdic O, Jager U, et al: Cross-priming of cytotoxic T cells promoted by apoptosis-inducing tumor cell reactive antibodies? J Clin Immunol 22: 124–130, 2002

    Article  PubMed  CAS  Google Scholar 

  54. Jander S, Schroeter M, D’Urso D, et al: Focal ischaemia of the rat brain elicits an unusual inflammatory response: early appearance of CD8+ macrophages/microglia Eur J Neurosci 10: 680–688, 1998

    Article  PubMed  CAS  Google Scholar 

  55. Morioka T, Baba T, Black KL, et al: Immunophenotypic analysis of infiltrating leukocytes and microglia in an experimental rat glioma Acta Neuropathol 83: 590–597, 1992

    Article  PubMed  CAS  Google Scholar 

  56. Perry VH, Gordon S Modulation of CD4 antigen on macrophages and microglia in rat brain J Exp Med 166: 1138–1143, 1987

    Article  PubMed  CAS  Google Scholar 

  57. Popovich PG, van Rooijen N, Hickey WF, et al: Hematogenous macrophages express CD8 and distribute to regions of lesion cavitation after spinal cord injury Exp Neurol 182: 275–287, 2003

    Article  PubMed  CAS  Google Scholar 

  58. Schroeter M, Jander S, Huitinga I, et al: CD8+ phagocytes in focal ischemia of the rat brain: predominant origin from hematogenous macrophages and targeting to areas of pannecrosis Acta Neuropathol (Berl) 101: 440–448, 2001

    CAS  Google Scholar 

  59. Weissenbock H, Hornig M, Hickey WF, et al: Microglial activation and neuronal apoptosis in Bornavirus infected neonatal Lewis rats Brain Pathol 10: 260–272, 2000

    Article  PubMed  CAS  Google Scholar 

  60. Hirji N, Lin TJ, Befus AD A novel CD8 molecule expressed by alveolar and peritoneal macrophages stimulates nitric oxide production J Immunol 158: 1833–1840, 1997

    PubMed  CAS  Google Scholar 

  61. Hirji N, Lin TJ, Bissonnette E, et al: Mechanisms of macrophage stimulation through CD8: macrophage CD8alpha and CD8beta induce nitric oxide production and associated killing of the parasite Leishmania major J Immunol 160: 6004–6011, 1998

    PubMed  CAS  Google Scholar 

  62. Frei K, Siepl C, Groscurth P, et al: Antigen presentation and tumor cytotoxicity by interferon-gamma-treated microglial cells Eur J Immunol 17: 1271–1278, 1987

    Article  PubMed  CAS  Google Scholar 

  63. Murata J, Ricciardi-Castagnoli P, Dessous L’Eglise Mange P, et al: Microglial cells induce cytotoxic effects toward colon carcinoma cells: measurement of tumor cytotoxicity with a gamma-glutamyl transpeptidase assay Int J Cancer 70: 169–174, 1997

    Article  PubMed  CAS  Google Scholar 

  64. Sutter A, Hekmat A, Luckenbach GA Antibody-mediated tumor cytotoxicity of microglia Pathobiology 59: 254–258, 1991

    Article  PubMed  CAS  Google Scholar 

  65. Aloisi F, De Simone R, Columba-Cabezas S, et al: Functional maturation of adult mouse resting microglia into an APC is promoted by granulocyte-macrophage colony-stimulating factor and interaction with Th1 cells J Immunol 164: 1705–1712, 2000

    PubMed  CAS  Google Scholar 

  66. Kulprathipanja NV, Kruse CA Microglia phagocytose alloreactive CTL-damaged 9L gliosarcoma cells J Neuroimmunol 153: 76–82, 2004

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This study was supported by the James S. McDonnell Foundation. The authors acknowledge Xeve Silver and AMRIS for assistance with MR imaging.

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Correspondence to Christopher L. Mariani.

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Mariani, C.L., Kouri, J.G. & Streit, W.J. Rejection of RG-2 gliomas is mediated by microglia and T lymphocytes. J Neurooncol 79, 243–253 (2006). https://doi.org/10.1007/s11060-006-9137-x

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  • DOI: https://doi.org/10.1007/s11060-006-9137-x

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