Combating immunosuppression in glioma

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

Bibliography

• 1  Stupp R, Mason WP, van den Bent MJ et al.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med.352,987–996 (2005).
  Medline CASGoogle Scholar
• 2  De Vleeschouwer S, van Gool SW, Van Calenbergh F: Immunotherapy for malignant gliomas: emphasis on strategies of active specific immunotherapy using autologous dendritic cells. Childs Nerv. Syst.21,7–18 (2005).
  MedlineGoogle Scholar
• 3  Bechmann I, Galea I, Perry VH: What is the blood–brain barrier (not)? Trends Immunol.28,5–11 (2007).
  Medline CASGoogle Scholar
• 4  Bechmann I, Priller J, Kovac A et al.: Immune surveillance of mouse brain perivascular spaces by blood-borne macrophages. Eur. J. Neurosci.14,1651–1658 (2001).
  Medline CASGoogle Scholar
• 5  Poduslo JF, Ramakrishnan M, Holasek SS et al.: In vivo targeting of antibody fragments to the nervous system for Alzheimer’s disease immunotherapy and molecular imaging of amyloid plaques. J. Neurochem.102,420–433 (2007).
  Medline CASGoogle Scholar
• 6  Engelhardt B, Ransohoff RM: The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol.26,485–495 (2005).
  Medline CASGoogle Scholar
• 7  Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC: CNS immune privilege: hiding in plain sight. Immunol. Rev.213,48–65 (2006).
  MedlineGoogle Scholar
• 8  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).
  Medline CASGoogle Scholar
• 9  Galea I, Bechmann I, Perry VH: What is immune privilege (not)? Trends Immunol.28,12–18 (2007).
  Medline CASGoogle Scholar
• 10  Fecci PE, Mitchell DA, Whitesides JF et al.: Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res.66,3294–3302 (2006).• Despite decreased absolute counts of CD4+ T cells and Tregs in peripheral blood of patients with malignant glioma, Treg fraction of remaining CD4+ compartment is increased. Increased Treg fraction correlates to immune deficits associated with glioma in vitro; Treg removal reverses these immune defects.
  Medline CASGoogle Scholar
• 11  Dix AR, Brooks WH, Roszman TL, Morford LA: Immune defects observed in patients with primary malignant brain tumors. J. Neuroimmunol.100,216–232 (1999).
  Medline CASGoogle Scholar
• 12  Mahaley MS Jr, Brooks WH, Roszman TL, Bigner DD, Dudka L, Richardson S: Immunobiology of primary intracranial tumors. Part 1: studies of the cellular and humoral general immune competence of brain-tumor patients. J. Neurosurg.46,467–476 (1977).
  MedlineGoogle Scholar
• 13  Young HF, Sakalas R, Kaplan AM: Inhibition of cell-mediated immunity in patients with brain tumors. Surg. Neurol.5,19–23 (1976).
  Medline CASGoogle Scholar
• 14  Brooks WH, Netsky MG, Normansell DE, Horwitz DA: Depressed cell-mediated immunity in patients with primary intracranial tumors. Characterization of a humoral immunosuppressive factor. J. Exp. Med.136,1631–1647 (1972).
  Medline CASGoogle Scholar
• 15  Elliott L, Brooks W, Roszman T: Role of interleukin-2 (IL-2) and IL-2 receptor expression in the proliferative defect observed in mitogen-stimulated lymphocytes from patients with gliomas. J. Natl Cancer Inst.78,919–922 (1987).
  Medline CASGoogle Scholar
• 16  Ashkenazi E, Deutsch M, Tirosh R, Weinreb A, Tsukerman A, Brodie C: A selective impairment of the IL-2 system in lymphocytes of patients with glioblastomas: increased level of soluble IL-2R and reduced protein tyrosine phosphorylation. Neuroimmunomodulation4,49–56 (1997).
  Medline CASGoogle Scholar
• 17  Elliott LH, Brooks WH, Roszman TL: Inability of mitogen-activated lymphocytes obtained from patients with malignant primary intracranial tumors to express high affinity interleukin 2 receptors. J. Clin. Invest.86,80–86 (1990).
  Medline CASGoogle Scholar
• 18  Brooks WH, Roszman TL, Rogers AS: Impairment of rosette-forming T lymphoctyes in patients with primary intracranial tumors. Cancer37,1869–1873 (1976).
  Medline CASGoogle Scholar
• 19  Young HF, Kaplan AM: Cellular immune deficiency in patients with glioblastoma. Surg. Forum27,476–478 (1976).
  Medline CASGoogle Scholar
• 20  Elliott L, Brooks W, Roszman T: Inhibition of anti-CD3 monoclonal antibody-induced T-cell proliferation by dexamethasone, isoproterenol, or prostaglandin E2 either alone or in combination. Cell Mol. Neurobiol.12,411–427 (1992).
  Medline CASGoogle Scholar
• 21  Roszman TL, Brooks WH: Immunobiology of primary intracranial tumours. III. Demonstration of a qualitative lymphocyte abnormality in patients with primary brain tumours. Clin. Exp. Immunol.39,395–402 (1980).
  Medline CASGoogle Scholar
• 22  Roszman TL, Brooks WH, Elliott LH: Immunobiology of primary intracranial tumors. VI. Suppressor cell function and lectin-binding lymphocyte subpopulations in patients with cerebral tumors. Cancer50,1273–1279 (1982).
  Medline CASGoogle Scholar
• 23  Huettner C, Czub S, Kerkau S, Roggendorf W, Tonn JC: Interleukin 10 is expressed in human gliomas in vivo and increases glioma cell proliferation and motility in vitro. Anticancer Res.17,3217–3224 (1997).
  Medline CASGoogle Scholar
• 24  Brenner AV, Linet MS, Fine HA et al.: History of allergies and autoimmune diseases and risk of brain tumors in adults. Int. J. Cancer99,252–259 (2002).
  Medline CASGoogle Scholar
• 25  Wiemels JL, Wiencke JK, Sison JD, Miike R, McMillan A, Wrensch M: History of allergies among adults with glioma and controls. Int. J. Cancer98,609–615 (2002).
  Medline CASGoogle Scholar
• 26  Wheeler CJ, Black KL, Liu G et al.: Thymic CD8⁺ T cell production strongly influences tumor antigen recognition and age-dependent glioma mortality. J. Immunol.171,4927–4933 (2003).
  Medline CASGoogle Scholar
• 27  Liau LM, Prins RM, Kiertscher SM et al.: Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin. Cancer Res.11,5515–5525 (2005).
  Medline CASGoogle Scholar
• 28  Akasaki Y, Liu G, Chung NH, Ehtesham M, Black KL, Yu JS: Induction of a CD4⁺ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma. J. Immunol.173,4352–4439 (2004).
  Medline CASGoogle Scholar
• 29  Fujita M, Zhu X, Sasaki K et al.: Inhibition of STAT3 promotes the efficacy of adoptive transfer therapy using type-1 CTLs by modulation of the immunological microenvironment in a murine intracranial glioma. J. Immunol.180,2089–2098 (2008).
  Medline CASGoogle Scholar
• 30  Parsa AT, Waldron JS, Panner A et al.: Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat. Med.13,84–88 (2007).
  Medline CASGoogle Scholar
• 31  Massague J: TGF-β signal transduction. Annu. Rev. Biochem.67,753–791 (1998).
  Medline CASGoogle Scholar
• 32  Platten M, Wick W, Weller M: Malignant glioma biology: role for TGF-β in growth, motility, angiogenesis, and immune escape. Microsc. Res. Tech.52,401–410 (2001).
  Medline CASGoogle Scholar
• 33  Hunter KE, Sporn MB, Davies AM: Transforming growth factor-βs inhibit mitogen-stimulated proliferation of astrocytes. Glia7,203–211 (1993).
  Medline CASGoogle Scholar
• 34  Rich JN, Zhang M, Datto MB, Bigner DD, Wang XF: Transforming growth factor-β-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. J. Biol. Chem.274,35053–35058 (1999).
  Medline CASGoogle Scholar
• 35  Vergeli M, Mazzanti B, Ballerini C, Gran B, Amaducci L, Massacesi L: Transforming growth factor-β 1 inhibits the proliferation of rat astrocytes induced by serum and growth factors. J. Neurosci. Res.40,127–133 (1995).
  Medline CASGoogle Scholar
• 36  Wesolowska A, Kwiatkowska A, Slomnicki L et al.: Microglia-derived TGF-β as an important regulator of glioblastoma invasion – an inhibition of TGF-β-dependent effects by shRNA against human TGF-β type II receptor. Oncogene27(7),918–930 (2007).
  MedlineGoogle Scholar
• 37  Paulus W, Baur I, Huettner C et al.: Effects of transforming growth factor-β 1 on collagen synthesis, integrin expression, adhesion and invasion of glioma cells. J. Neuropathol. Exp. Neurol.54,236–244 (1995).
  Medline CASGoogle Scholar
• 38  Koochekpour S, Merzak A, Pilkington GJ: Vascular endothelial growth factor production is stimulated by gangliosides and TGF-β isoforms in human glioma cells in vitro. Cancer Lett.102,209–215 (1996).
  Medline CASGoogle Scholar
• 39  Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA: A role for TGF-β in the generation and expansion of CD4⁺CD25⁺ regulatory T cells from human peripheral blood. J. Immunol.166,7282–7289 (2001).
  Medline CASGoogle Scholar
• 40  Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF: Cutting edge: TGF-β induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J. Immunol.172,5149–5153 (2004).
  Medline CASGoogle Scholar
• 41  de Visser KE, Kast WM: Effects of TGF-β on the immune system: implications for cancer immunotherapy. Leukemia13,1188–1199 (1999).
  Medline CASGoogle Scholar
• 42  Liu Y, Wang Q, Kleinschmidt-DeMasters BK, Franzusoff A, Ng KY, Lillehei KO: TGF-β2 inhibition augments the effect of tumor vaccine and improves the survival of animals with pre-established brain tumors. J. Neurooncol.81,149–162 (2007).
  Medline CASGoogle Scholar
• 43  Hau P, Jachimczak P, Schlingensiepen R et al.: Inhibition of TGF-β2 with AP 12009 in recurrent malignant gliomas: from preclinical to Phase I/II studies. Oligonucleotides17,201–212 (2007).• AP 12009 is an antisense oligodeoxynucleotide that binds to TGF-β2 mRNA and prevents its translation into a gene product. In Phase I/II clinical trials, intratumoral infusions of AP 12009 were shown to be safe and well-tolerated in patients with recurrent malignant glioma. Several patients experienced prolonged survival.
  Medline CASGoogle Scholar
• 44  Uhl M, Aulwurm S, Wischhusen J et al.: SD-208, a novel transforming growth factor β receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res.64,7954–7961 (2004).• In a murine model for glioma, the TGF-β receptor I kinase inhibitor, SX-007, increased median survival time and reversed some of the TGF-β-induced immune defects associated with glioma.
  Medline CASGoogle Scholar
• 45  Tran TT, Uhl M, Ma JY et al.: Inhibiting TGF-β signaling restores immune surveillance in the SMA-560 glioma model. Neuro Oncol.9,259–270 (2007).
  Medline CASGoogle Scholar
• 46  Wojtowicz-Praga S: Reversal of tumor-induced immunosuppression by TGF-β inhibitors. Invest. New Drugs21,21–32 (2003).
  Medline CASGoogle Scholar
• 47  Dong M, How T, Kirkbride KC et al.: The type III TGF-β receptor suppresses breast cancer progression. J. Clin. Invest.117,206–217 (2007).
  Medline CASGoogle Scholar
• 48  Hempel N, How T, Dong M, Murphy SK, Fields TA, Blobe GC: Loss of β-glycan expression in ovarian cancer: role in motility and invasion. Cancer Res.67,5231–5238 (2007).
  Medline CASGoogle Scholar
• 49  Sharifi N, Hurt EM, Kawasaki BT, Farrar WL: TGFBR3 loss and consequences in prostate cancer. Prostate67,301–311 (2007).
  MedlineGoogle Scholar
• 50  Biswas S, Guix M, Rinehart C et al.: Inhibition of TGF-β with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J. Clin. Invest.117,1305–1313 (2007).
  Medline CASGoogle Scholar
• 51  Nam JS, Suchar AM, Kang MJ et al.: Bone sialoprotein mediates the tumor cell-targeted prometastatic activity of transforming growth factor β in a mouse model of breast cancer. Cancer Res.66,6327–6335 (2006).
  Medline CASGoogle Scholar
• 52  Liu VC, Wong LY, Jang T et al.: Tumor evasion of the immune system by converting CD4⁺CD25^- T cells into CD4⁺CD25⁺ T regulatory cells: role of tumor-derived TGF-β. J. Immunol.178,2883–2892 (2007).
  Medline CASGoogle Scholar
• 53  Nomura T, Sakaguchi S: Naturally arising CD25⁺CD4⁺regulatory T cells in tumor immunity. Curr. Top. Microbiol. Immunol.293,287–302 (2005).
  Medline CASGoogle Scholar
• 54  Randolph DA, Fathman CG: Cd4⁺Cd25⁺ regulatory T cells and their therapeutic potential. Annu. Rev. Med.57,381–402 (2006).
  Medline CASGoogle Scholar
• 55  Baecher-Allan C, Anderson DE: Regulatory cells and human cancer. Semin. Cancer Biol.16,98–105 (2006).
  Medline CASGoogle Scholar
• 56  Thornton, AM, Shevach EM: CD4⁺CD25⁺ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med.188,287–296 (1998).
  Medline CASGoogle Scholar
• 57  Piccirillo CA, Shevach EM: Cutting edge: control of CD8⁺ T cell activation by CD4⁺CD25⁺ immunoregulatory cells. J. Immunol.167,1137–1140 (2001).
  Medline CASGoogle Scholar
• 58  Dieckmann D, Bruett CH, Ploettner H, Lutz MB, Schuler G: Human CD4⁺CD25⁺ regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells [corrected]. J. Exp. Med.196,247–253 (2002).
  Medline CASGoogle Scholar
• 59  Liyanage UK, Moore TT, Joo HG et al.: Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J. Immunol.169,2756–2761 (2002).
  Medline CASGoogle Scholar
• 60  Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H: Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin. Cancer Res.9,4404–4408 (2003).
  MedlineGoogle Scholar
• 61  Rosenberg SA, Sportes C, Ahmadzadeh M et al.: IL-7 administration to humans leads to expansion of CD8⁺ and CD4⁺ cells but a relative decrease of CD4⁺ T-regulatory cells. J. Immunother. (1997) 29,313–319 (2006).
  Medline CASGoogle Scholar
• 62  Fecci PE, Sweeney AE, Grossi PM et al.: Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells. Clin. Cancer Res.12,4294–4305 (2006).
  Medline CASGoogle Scholar
• 63  Grauer OM, Nierkens S, Bennink E et al.: CD4⁺FoxP3⁺ regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo. Int. J. Cancer121,95–105 (2007).• Glioma-bearing mice show a decrease in CD4+ T cells and Treg absolute number in peripheral blood, while Tregfraction is increased; the reverse is seen in bone marrow. In a murine model for glioma, systemic administration of anti-CD25 mAb inhibited the suppressive action of Tregs, without completely eliminating the Treg fraction. Combining anti-CD25 mAb with tumor RNA-pulsed dendritic cell vaccination led to tumor rejection in 100% of mice.
  Medline CASGoogle Scholar
• 64  Powell DJ Jr, Felipe-Silva A, Merino MJ et al.: Administration of a CD25-directed immunotoxin, LMB-2, to patients with metastatic melanoma induces a selective partial reduction in regulatory T cells in vivo. J. Immunol.179,4919–4928 (2007).
  Medline CASGoogle Scholar
• 65  Ochiai H, Archer GE, Herndon JE 2nd et al.: EGFRvIII-targeted immunotoxin induces antitumor immunity that is inhibited in the absence of CD4⁺ and CD8⁺ T cells. Cancer Immunol. Immunother.57(1),115–121 (2007).
  MedlineGoogle Scholar
• 66  Litzinger MT, Fernando R, Curiel TJ, Grosenbach DW, Schlom J, Palena C: The IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. Blood110(9),3192–3201 (2007).
  Medline CASGoogle Scholar
• 67  Mahnke K, Schonfeld K, Fondel S et al.: Depletion of CD4⁺CD25⁺ human regulatory T cells in vivo: kinetics of Treg depletion and alterations in immune functions in vivo and in vitro. Int. J. Cancer120,2723–2733 (2007).
  Medline CASGoogle Scholar
• 68  Attia P, Maker AV, Haworth LR, Rogers-Freezer L, Rosenberg SA: Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma. J. Immunother.28,582–592 (2005).
  Medline CASGoogle Scholar
• 69  Cranmer LD, Hersh E: The role of the CTLA4 blockade in the treatment of malignant melanoma. Cancer Invest.25,613–631 (2007).
  Medline CASGoogle Scholar
• 70  Fecci PE, Ochiai H, Mitchell DA et al.: Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4⁺ T cell compartment without affecting regulatory T-cell function. Clin. Cancer Res.13,2158–2167 (2007).• Systemic administration of monoclonal antibody to CTLA-4 led to prolonged survival in a murine model for glioma. CTLA-4 blockade also re-established normal CD4 counts and proliferative activity and prevented increase in Treg fraction; benefits were due to effect on CD4+CD25- T cells only, and not on Tregs.
  Medline CASGoogle Scholar
• 71  Phan GQ, Yang JC, Sherry RM et al.: Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc. Natl Acad. Sci. USA100,8372–8377 (2003).
  Medline CASGoogle Scholar
• 72  Attia P, Phan GQ, Maker AV et al.: Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J. Clin. Oncol.23,6043–6053 (2005).
  Medline CASGoogle Scholar
• 73  Maker AV, Phan GQ, Attia P et al.: Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a Phase I/II study. Ann. Surg. Oncol.12,1005–1016 (2005).
  MedlineGoogle Scholar
• 74  Nocentini G, Ronchetti S, Cuzzocrea S, Riccardi C: GITR/GITRL: more than an effector T cell co-stimulatory system. Eur. J. Immunol.37,1165–1169 (2007).
  Medline CASGoogle Scholar
• 75  Ko K, Yamazaki S, Nakamura K et al.: Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3⁺CD25⁺CD4⁺ regulatory T cells. J. Exp. Med.202,885–891 (2005).
  Medline CASGoogle Scholar
• 76  Tuyaerts S, van Meirvenne S, Bonehill A et al.: Expression of human GITRL on myeloid dendritic cells enhances their immunostimulatory function but does not abrogate the suppressive effect of CD4⁺CD25⁺ regulatory T cells. J. Leukoc. Biol.82,93–105 (2007).
  Medline CASGoogle Scholar
• 77  Nair S, Boczkowski D, Fassnacht M, Pisetsky D, Gilboa E: Vaccination against the forkhead family transcription factor Foxp3 enhances tumor immunity. Cancer Res.67,371–380 (2007).• Vaccination against foxp3 in a murine model of glioma led to a Foxp3-specific CTL response and a reduction in number of Tregsintratumorally, but not in the periphery, whereas administration of anti-CD25 antibody caused Tregdepletion in both locations.
  Medline CASGoogle Scholar
• 78  Heimberger AB, Sun W, Hussain SF et al.: Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: case study. Neuro. Oncol.10,98–103 (2008).
  Medline CASGoogle Scholar
• 79  Comes A, Rosso O, Orengo AM et al.: CD25⁺ regulatory T cell depletion augments immunotherapy of micrometastases by an IL-21-secreting cellular vaccine. J. Immunol.176,1750–1758 (2006).
  Medline CASGoogle Scholar
• 101  Description of the Safety and Efficacy Study of GC1008 to Treat Renal Cell Carcinoma or Malignant Melanoma from the ClinicalTrials.gov website http://clinicaltrials.gov/ct/show/NCT00356460?order=2)
  Google Scholar