Top

Published in:

01-05-2007 | Original Article

Induction of apoptosis and immune response by all-trans retinoic acid plus interferon-gamma in human malignant glioblastoma T98G and U87MG cells

Authors: Azizul Haque, Arabinda Das, Laela M. Hajiaghamohseni, Austin Younger, Naren L. Banik, Swapan K. Ray

Published in: Cancer Immunology, Immunotherapy | Issue 5/2007

Abstract

Glioblastoma is the most common and highly malignant brain tumor. It is also one among the most therapy-resistant human neoplasias. Patients die within a year of diagnosis despite the use of available treatment strategies such as surgery, radiotherapy, and chemotherapy. Thus, there is a critical need to find a novel therapeutic strategy for treating this disease. Here, we have investigated the molecular mechanisms for induction of apoptosis as well as for activation of immune components in human malignant glioblastoma T98G and U87MG cells following treatment with all-trans retinoic acid (ATRA) plus interferon-gamma (IFN-γ). Treatment of glioblastoma cells with ATRA alone prevented cell proliferation and induced astrocytic differentiation, while IFN-γ alone induced apoptosis and modulated expression of human leukocyte antigen (HLA) class II molecules such as HLA-DRα, HLA-DR complex, invariant chain (Ii), HLA-DM (an important catalyst of the class II-peptide loading), and gamma interferon-inducible lysosomal thiol-reductase (GILT). Interestingly, both T98G and U87MG cells showed more increase in apoptosis with expression of the HLA class II components for an effective immune response following treatment with ATRA plus IFN-γ than with IFN-γ alone. Apoptotic mode of cell death was confirmed morphologically by Wright staining and biochemically by measuring an increase in caspase-3 activity. While conversion of tumor cells into HLA class II+/Ii- cells by stimulation with the helper CD4+ T cells is thought to be challenging, this study reports for the first time that treatment of glioblastoma cells with ATRA plus IFN-γ can simultaneously enhance apoptosis and expression of the HLA class II immune components with a marked suppression of Ii expression. Taken together, this study suggests that induction of apoptosis and immune components of the HLA class II pathway by ATRA plus IFN-γ may be a promising chemoimmunotherapeutic strategy for treatment of human malignant glioblastoma.

Akasaki Y, Liu G, Chung NH, Ehtesham M, Black KL, Yu JS (2004) Induction of a CD4+ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma. J Immunol 173:4352–4359PubMed

Anderson HA, Roche PA (1998) Phosphorylation regulates the delivery of MHC class II invariant chain complexes to antigen processing compartments. J Immunol 160:4850–4858PubMed

Arneson LS, Katz JF, Liu M, Sant AJ (2001) Hydrogen bond integrity between MHC class II molecules and bound peptide determines the intracellular fate of MHC class II molecules. J Immunol 167:6939–6946PubMed

Avva RR, Cresswell P (1994) In vivo and in vitro formation and dissociation of HLA-DR complexes with invariant chain-derived peptides. Immunity 1:763–774CrossRefPubMed

Beers C, Burich A, Kleijmeer MJ, Griffith JM, Wong P, Rudensky AY (2005) Cathepsin S controls MHC class II-mediated antigen presentation by epithelial cells in vivo. J Immunol 174:1205–1212PubMed

Blum JS, Cresswell P (1988) Role for intracellular proteases in the processing and transport of class II HLA antigens. Proc Natl Acad Sci USA 85:3975–3979CrossRefPubMed

Brachet V, Raposo G, Amigorena S, Mellman I (1997) Ii chain controls the transport of major histocompatibility complex class II molecules to and from lysosomes. J Cell Biol 137:51–65CrossRefPubMed

Busch R, Rinderknecht CH, Roh S, Lee AW, Harding JJ, Burster T, Hornell TM, Mellins ED (2005) Achieving stability through editing and chaperoning: regulation of MHC class II peptide binding and expression. Immunol Rev 207:242–260CrossRefPubMed

Cetin N, Dienel G, Gokden M (2005) CD117 expression in glial tumors. J Neurooncol 75:195–202CrossRefPubMed

10.

Cresswell P (1996) Invariant chain structure and MHC class II function. Cell 84:505–507CrossRefPubMed

11.

Das A, Sribnick EA, Wingrave JM, Del Re AM, Woodward JJ, Appel SH, Banik NL, Ray SK (2005) Calpain activation in apoptosis of ventral spinal cord 4.1 (VSC4.1) motoneurons exposed to glutamate: calpain inhibition provides functional neuroprotection. J Neurosci Res 81:551–562CrossRefPubMed

12.

Das A, Banik NL, Patel SJ, Ray SK (2004) Dexamethasone protected human glioblastoma U87MG cells from temozolomide induced apoptosis by maintaining Bax:Bcl-2 ratio and preventing proteolytic activities. Mol Cancer 3:36CrossRefPubMed

13.

Das A, Garner DP, Del Re AM, Woodward JJ, Kumar DM, Agarwal N, Banik NL, Ray SK (2006) Calpeptin provides functional neuroprotection to rat retinal ganglion cells following Ca²⁺influx. Brain Res 1084:146–157CrossRefPubMed

14.

Degener T, Momburg F, Moller P (1988) Differential expression of HLA-DR, HLA-DP, HLA-DQ and associated invariant chain (Ii) in normal colorectal mucosa, adenoma and carcinoma. Virchows Arch A Pathol Anat Histopathol 412:315–422CrossRefPubMed

15.

Denzin LK, Hammond C, Cresswell P (1996) HLA-DM interactions with intermediates in HLA-DR maturation and a role for HLA-DM in stabilizing empty HLA-DR molecules. J Exp Med 184:2153–2165CrossRefPubMed

16.

Denzin LK, Sant’Angelo DB, Hammond C, Surman MJ, Cresswell P (1997) Negative regulation by HLA-DO of MHC class II-restricted antigen processing. Science 278:106–109CrossRefPubMed

17.

Haque A, Blum JS (2005) New insights in antigen processing and epitope selection: development of novel immunotherapeutic strategies for cancer, autoimmunity and infectious diseases. J Biol Regul Homeost Agents 19:93–104PubMed

18.

Haque MA, Hawes JW, Blum JS (2001) Cysteinylation of MHC class II ligands: peptide endocytosis and reduction within APC influences T cell recognition. J Immunol 166:4543–4551PubMed

19.

Haque MA, Li P, Jackson SK, Zarour HM, Hawes JW, Phan UT, Maric M, Cresswell P, Blum JS (2002) Absence of gamma-interferon-inducible lysosomal thiol reductase in melanomas disrupts T cell recognition of select immunodominant epitopes. J Exp Med 195:1267–1277CrossRefPubMed

20.

Hart DN (1997) Dendritic cells: unique leukocyte populations which control the primary immune response. Blood 90:3245–3287PubMed

21.

Hatano M, Eguchi J, Tatsumi T, Kuwashima N, Dusak JE, Kinch MS, Pollack IF, Hamilton RL, Storkus WJ, Okada H (2005) EphA2 as a glioma-associated antigen: a novel target for glioma vaccines. Neoplasia 7:717–722CrossRefPubMed

22.

Hong SJ, Kim TY, Kang SY, Yu JR, Song KY, Cho SY (2002) Clonorchis sinensis: immunolocalization of 26 kDa glutathione S-transferase in adult worms. Exp Parasitol 102:191–193PubMed

23.

Hume DA, Fairlie DP (2005) Therapeutic targets in inflammatory disease. Curr Med Chem 12:2925–2929CrossRefPubMed

24.

Kikuchi T, Akasaki Y, Irie M, Homma S, Abe T, Ohno T (2001) Results of a phase I clinical trial of vaccination of glioma patients with fusions of dendritic and glioma cells. Cancer Immunol Immunother 50:337–344CrossRefPubMed

25.

Li P, Haque MA, Blum JS (2002) Role of disulfide bonds in regulating antigen processing and epitope selection. J Immunol 169:2444–2450PubMed

26.

Lich JD, Jayne JA, Zhou D, Elliott JF, Blum JS (2003) Editing of an immunodominant epitope of glutamate decarboxylase by HLA-DM. J Immunol 171:853–859PubMed

27.

Liu G, Ying H, Zeng G, Wheeler CJ, Black KL, Yu JS (2004) HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells. Cancer Res 64:4980–4986CrossRefPubMed

28.

Maric MA, Taylor MD, Blum JS (1994) Endosomal aspartic proteinases are required for invariant-chain processing. Proc Natl Acad Sci USA 91:2171–2175CrossRefPubMed

29.

Matloubian M, Concepcion RJ, Ahmed R (1994) CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol 68:8056–8063PubMed

30.

Mautner J, Jaffee EM, Pardoll DM (2005) Tumor-specific CD4+ T cells from a patient with renal cell carcinoma recognize diverse shared antigens. Int J Cancer 115:752–759CrossRefPubMed

31.

Mirandola P, Sponzilli I, Solenghi E, Micheloni C, Rinaldi L, Gobbi G, Vitale M (2006) Down-regulation of human leukocyte antigen class I and II and beta 2-microglobulin expression in human herpesvirus-7-infected cells. J Infect Dis 193:917–926CrossRefPubMed

32.

Nakagawa TY, Rudensky AY (1999) The role of lysosomal proteinases in MHC class II-mediated antigen processing and presentation. Immunol Rev 172:121–129CrossRefPubMed

33.

Nicholson MJ, Moradi B, Seth NP, Xing X, Cuny GD, Stein RL, Wucherpfennig KW (2006) Small molecules that enhance the catalytic efficiency of HLA-DM. J Immunol 176:4208–4220PubMed

34.

Nutt CL, Betensky RA, Brower MA, Batchelor TT, Louis DN, Stemmer-Rachamimov AO (2005) YKL-40 is a differential diagnostic marker for histologic subtypes of high-grade gliomas. Clin Cancer Res 11:2258–2264CrossRefPubMed

35.

O’Donnell PW, Haque A, Klemsz MJ, Kaplan MH, Blum JS (2004) Induction of the antigen-processing enzyme IFN-γ-inducible lysosomal thiol reductase in melanoma cells is STAT1-dependent but CIITA-independent. J Immunol 173:731–735PubMed

36.

Oldford SA, Robb JD, Watson PH, Drover S (2004) HLA-DRB alleles are differentially expressed by tumor cells in breast carcinoma. Int J Cancer 112:399–406CrossRefPubMed

37.

Pallasch CP, Struss AK, Munnia A, Konig J, Steudel WI, Fischer U, Meese E (2005) Autoantibodies against GLEA2 and PHF3 in glioblastoma: tumor-associated autoantibodies correlated with prolonged survival. Int J Cancer 117:456–459CrossRefPubMed

38.

Pathak SS, Lich JD, Blum JS (2001) Editing of recycling class II: peptide complexes by HLA-DM. J Immunol 167:632–635PubMed

39.

Plautz GE, Miller DW, Barnett GH, Stevens GH, Maffett S, Kim J, Cohen PA, Shu S (2000) T cell adoptive immunotherapy of newly diagnosed gliomas. Clin Cancer Res 6:2209–2218PubMed

40.

Rangel LB, Agarwal R, Sherman-Baust CA, Mello-Coelho V, Pizer ES, Ji H, Taub DD, Morin PJ (2004) Anomalous expression of the HLA-DR α and β chains in ovarian and other cancers. Cancer Biol Ther 3:1021–1027PubMedCrossRef

41.

Ray SK, Wilford GG, Crosby CV, Hogan EL, Banik NL (1999) Diverse stimuli induce calpain overexpression and apoptosis in C6 glioma cells. Brain Res 829:18–27CrossRefPubMed

42.

Roth W, Weller M (1999) Chemotherapy and immunotherapy of malignant glioma: molecular mechanisms and clinical perspectives. Cell Mol Life Sci 56:481–506CrossRefPubMed

43.

Rudensky AY, Maric M, Eastman S, Shoemaker L, DeRoos PC, Blum JS (1994) Intracellular assembly and transport of endogenous peptide-MHC class II complexes. Immunity 1:585–594CrossRefPubMed

44.

Shi B, Vinyals A, Alia P, Broceno C, Chen F, Adrover M, Gelpi C, Price JE, Fabra A (2006) Differential expression of MHC class II molecules in highly metastatic breast cancer cells is mediated by the regulation of the CIITA transcription implication of CIITA in tumor and metastasis development. Int J Biochem Cell Biol 38:544–562CrossRefPubMed

45.

Siegel RM (2006) Caspases at the crossroads of immune-cell life and death. Nat Rev Immunol 6:308–317CrossRefPubMed

46.

Simeone AM, Tari AM (2004) How retinoids regulate breast cancer cell proliferation and apoptosis. Cell Mol Life Sci 61:1475–1484CrossRefPubMed

47.

Sinnathamby G, Maric M, Cresswell P, Eisenlohr LC (2004) Differential requirements for endosomal reduction in the presentation of two H2-E(d)-restricted epitopes from influenza hemagglutinin. J Immunol 172:6607–6614PubMed

48.

Skurkovich B (2002) Recommendations for parents adopting an infant with chronic hepatitis B. Pediatr Infect Dis J 21:1180–1181PubMed

49.

Surawicz TS, Davis F, Freels S, Laws ER Jr, Menck HR (1998) Brain tumor survival: results from the National Cancer Data Base. J Neurooncol 40:151–160CrossRefPubMed

50.

Thompson JA, Dissanayake SK, Ksander BR, Knutson KL, Disis ML, Ostrand-Rosenberg S (2006) Tumor cells transduced with the MHC class II transactivator and CD80 activate tumor-specific CD4+ T cells whether or not they are silenced for invariant chain. Cancer Res 66:1147–1154CrossRefPubMed

51.

van der Bruggen P, Van den Eynde BJ (2006) Processing and presentation of tumor antigens and vaccination strategies. Curr Opin Immunol 18:98–104CrossRefPubMed

52.

Villarroel-Dorrego M, Speight PM, Barrett AW (2005) Expression of major histocompatibility complex class II and costimulatory molecules in oral carcinomas in vitro. Med Oral Patol Oral Cir Bucal 10:188–195PubMed

53.

Weber DA, Dao CT, Jun J, Wigal JL, Jensen PE (2001) Transmembrane domain-mediated colocalization of HLA-DM and HLA-DR is required for optimal HLA-DM catalytic activity. J Immunol 167:5167–5174PubMed

54.

Wischhusen J, Jung G, Radovanovic I, Beier C, Steinbach JP, Rimner A, Huang H, Schulz JB, Ohgaki H, Aguzzi A, Rammensee HG, Weller M (2002) Identification of CD70-mediated apoptosis of immune effector cells as a novel immune escape pathway of human glioblastoma. Cancer Res 62:2592–2599PubMed

55.

Zehbe I, Hohn H, Pilch H, Neukirch C, Freitag K, Maeurer MJ (2005) Differential MHC class II component expression in HPV-positive cervical cancer cells: implication for immune surveillance. Int J Cancer 117:807–815CrossRefPubMed

Title: Induction of apoptosis and immune response by all-trans retinoic acid plus interferon-gamma in human malignant glioblastoma T98G and U87MG cells
Authors: Azizul Haque
Arabinda Das
Laela M. Hajiaghamohseni
Austin Younger
Naren L. Banik
Swapan K. Ray
Publication date: 01-05-2007
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 5/2007
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-006-0219-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2007

Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients

Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion

HLA-A0201 positive pancreatic cell lines: new findings and discrepancies

Activation of complement C3, C5, and C9 genes in tumors treated by photodynamic therapy

Vaccination against prostate cancer using a live tissue factor deficient cell line in Lobund–Wistar rats

Functional CD8+ T cells infiltrate into nonsmall cell lung carcinoma

Keynote webinar | Spotlight on antibody–drug conjugates in cancer