class II transactivator; glioblastoma; natural killer cells; tumor microenvironment; tumor-associated macrophages; tumor-infiltrating lymphocytes; Oncology; Cancer Research
Abstract :
[en] Background: The major histocompatibility complex type II is downregulated in glioblastoma (GB) due to the silencing of the major transcriptional regulator class II transactivator (CIITA). We investigated the pro-immunogenic potential of CIITA overexpression in mouse and human GB. Methods: The intracerebral growth of wildtype GL261-WT cells was assessed following contralateral injection of GL261-CIITA cells or flank injections with GL261-WT or GL261-CIITA cells. Splenocytes obtained from mice implanted intracerebrally with GL261-WT, GL261-CIITA cells or phosphate buffered saline (PBS) were transferred to other mice and subsequently implanted intracerebrally with GL261-WT. Human GB cells and (syngeneic) GB-infiltrating immune cells were isolated from surgical samples and co-cultured with GB cells expressing CIITA or not, followed by RT-qPCR assessment of the expression of key immune regulators. Results: Intracerebral vaccination of GL261-CIITA significantly reduced the subsequent growth of GL261-WT cells implanted contralaterally. Vaccination with GL261-WT or -CIITA subcutaneously, however, equivalently retarded the intracerebral growth of GL261 cells. Adoptive cell transfer experiments showed a similar antitumor potential of lymphocytes harvested from mice implanted intracerebrally with GL261-WT or -CIITA. Human GB-infiltrating myeloid cells and lymphocytes were not activated when cultured with CIITA-expressing GB cells. Tumor-infiltrating NK cells remained mostly inactivated when in co-culture with GB cells, regardless of CIITA. Conclusion: these results question the therapeutic potential of CIITA-mediated immunotherapy in glioblastoma.
Disciplines :
Genetics & genetic processes
Author, co-author :
Tan, A. Katherine; Department of Translational Neuroscience, University Medical Center Utrecht (UMCU) Brain Center, Utrecht University, Utrecht, Netherlands
Henry, Aurélie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Génétique humaine
Goffart, Nicolas ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biochimie et physiologie générales, et biochimie humaine
van Logtestijn, Sofie; Department of Translational Neuroscience, University Medical Center Utrecht (UMCU) Brain Center, Utrecht University, Utrecht, Netherlands
Bours, Vincent ; Université de Liège - ULiège > GIGA > GIGA Cancer - Human Genetics
Hol, Elly M. ; Department of Translational Neuroscience, University Medical Center Utrecht (UMCU) Brain Center, Utrecht University, Utrecht, Netherlands
Robe, Pierre ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Génétique humaine ; Department of Translational Neuroscience, University Medical Center Utrecht (UMCU) Brain Center, Utrecht University, Utrecht, Netherlands ; Department of Neurosurgery, University Medical Center Utrecht (UMCU) Brain Center, Utrecht University, Utrecht, Netherlands
Language :
English
Title :
Limited Effects of Class II Transactivator-Based Immunotherapy in Murine and Human Glioblastoma
Publication date :
2024
Journal title :
Cancers
eISSN :
2072-6694
Publisher :
Multidisciplinary Digital Publishing Institute (MDPI)
This research was funded by Fonds de la Recherche Scientifique of Belgium grants (8.4628.16, 7.4639.17) and a Ton & Patricia Bohnenn Fund for Neuro-Oncology Research grant. Ton & Patricia Bohnenn Fund for Neuro-Oncology Research
Louis D.N. Perry A. Reifenberger G. von Deimling A. Figarella-Branger D. Cavenee W.K. Ohgaki H. Wiestler O.D. Kleihues P. Ellison D.W. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A Summary Acta Neuropathol. 2016 131 803 820 10.1007/s00401-016-1545-1
Stupp R. Mason W.P. van den Bent M.J. Weller M. Fisher B. Taphoorn M.J.B. Belanger K. Brandes A.A. Marosi C. Bogdahn U. et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma N. Engl. J. Med. 2005 352 987 996 10.1056/NEJMoa043330
Stupp R. Hegi M.E. Mason W.P. van den Bent M.J. Taphoorn M.J. Janzer R.C. Ludwin S.K. Allgeier A. Fisher B. Belanger K. et al. Effects of Radiotherapy with Concomitant and Adjuvant Temozolomide versus Radiotherapy Alone on Survival in Glioblastoma in a Randomised Phase III Study: 5-Year Analysis of the EORTC-NCIC Trial Lancet Oncol. 2009 10 459 466 10.1016/S1470-2045(09)70025-7
Stupp R. Taillibert S. Kanner A. Read W. Steinberg D.M. Lhermitte B. Toms S. Idbaih A. Ahluwalia M.S. Fink K. et al. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma JAMA 2017 318 2306 10.1001/jama.2017.18718
Jakovlevs A. Vanags A. Gardovskis J. Strumfa I. Molecular Classification of Diffuse Gliomas Pol. J. Pathol. 2019 70 246 258 10.5114/pjp.2019.93126
Diaz R.J. Ali S. Qadir M.G. De La Fuente M.I. Ivan M.E. Komotar R.J. The Role of Bevacizumab in the Treatment of Glioblastoma J. Neuro-Oncol. 2017 133 455 467 10.1007/s11060-017-2477-x
Lim M. Weller M. Chiocca E.A. Current State of Immune-Based Therapies for Glioblastoma Am. Soc. Clin. Oncol. Educ. Book 2016 35 e132 e139 10.1200/EDBK_159084
Medikonda R. Dunn G. Rahman M. Fecci P. Lim M. A Review of Glioblastoma Immunotherapy J. Neuro-Oncol. 2021 151 41 53 10.1007/s11060-020-03448-1
Scherm A. Ippen F.M. Hau P. Baurecht H. Wick W. Gempt J. Knüttel H. Leitzmann M.F. Seliger C. Targeted Therapies in Patients with Newly Diagnosed Glioblastoma—A Systematic Meta-analysis of Randomized Clinical Trials Int. J. Cancer 2023 152 2373 2382 10.1002/ijc.34433
Weenink B. French P.J. Sillevis Smitt P.A.E. Debets R. Geurts M. Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives Cancers 2020 12 751 10.3390/cancers12030751
Brown N.F. Carter T.J. Ottaviani D. Mulholland P. Harnessing the Immune System in Glioblastoma Br. J. Cancer 2018 119 1171 1181 10.1038/s41416-018-0258-8
Accolla R.S. Ramia E. Tedeschi A. Forlani G. CIITA-Driven MHC Class II Expressing Tumor Cells as Antigen Presenting Cell Performers: Toward the Construction of an Optimal Anti-Tumor Vaccine Front. Immunol. 2019 10 1806 10.3389/fimmu.2019.01806
Hambardzumyan D. Bergers G. Glioblastoma: Defining Tumor Niches Trends Cancer 2015 1 252 265 10.1016/j.trecan.2015.10.009
Matias D. Balça-Silva J. da Graça G.C. Wanjiru C.M. Macharia L.W. Nascimento C.P. Roque N.R. Coelho-Aguiar J.M. Pereira C.M. Dos Santos M.F. et al. Microglia/Astrocytes–Glioblastoma Crosstalk: Crucial Molecular Mechanisms and Microenvironmental Factors Front. Cell. Neurosci. 2018 12 235 10.3389/fncel.2018.00235
Sørensen M.D. Dahlrot R.H. Boldt H.B. Hansen S. Kristensen B.W. Tumour-Associated Microglia/Macrophages Predict Poor Prognosis in High-Grade Gliomas and Correlate with an Aggressive Tumour Subtype Neuropathol. Appl. Neurobiol. 2018 44 185 206 10.1111/nan.12428
Szulzewsky F. Pelz A. Feng X. Synowitz M. Markovic D. Langmann T. Holtman I.R. Wang X. Eggen B.J.L. Boddeke H.W.G.M. et al. Glioma-Associated Microglia/Macrophages Display an Expression Profile Different from M1 and M2 Polarization and Highly Express Gpnmb and Spp1 PLoS ONE 2015 10 e0116644 10.1371/journal.pone.0116644
Woroniecka K. Chongsathidkiet P. Rhodin K. Kemeny H. Dechant C. Farber S.H. Elsamadicy A.A. Cui X. Koyama S. Jackson C. et al. T-Cell Exhaustion Signatures Vary with Tumor Type and Are Severe in Glioblastoma Clin. Cancer Res. 2018 24 4175 4186 10.1158/1078-0432.CCR-17-1846
Woroniecka K.I. Rhodin K.E. Chongsathidkiet P. Keith K.A. Fecci P.E. T-Cell Dysfunction in Glioblastoma: Applying a New Framework Clin. Cancer Res. 2018 24 3792 3802 10.1158/1078-0432.CCR-18-0047
Woroniecka K. Fecci P.E. T-Cell Exhaustion in Glioblastoma Oncotarget 2018 9 35287 35288 10.18632/oncotarget.26228
Filley A.C. Henriquez M. Dey M. Recurrent Glioma Clinical Trial, CheckMate-143: The Game Is Not over Yet Oncotarget 2017 8 91779 91794 10.18632/oncotarget.21586
Omuro A. Vlahovic G. Lim M. Sahebjam S. Baehring J. Cloughesy T. Voloschin A. Ramkissoon S.H. Ligon K.L. Latek R. et al. Nivolumab with or without Ipilimumab in Patients with Recurrent Glioblastoma: Results from Exploratory Phase I Cohorts of CheckMate 143 Neuro Oncol. 2018 20 674 686 10.1093/neuonc/nox208 29106665
Strickler J.H. Hanks B.A. Khasraw M. Tumor Mutational Burden as a Predictor of Immunotherapy Response: Is More Always Better? Clin. Cancer Res. 2021 27 1236 1241 10.1158/1078-0432.CCR-20-3054 33199494
Forlani G. Michaux J. Pak H. Huber F. Marie Joseph E.L. Ramia E. Stevenson B.J. Linnebacher M. Accolla R.S. Bassani-Sternberg M. CIITA-Transduced Glioblastoma Cells Uncover a Rich Repertoire of Clinically Relevant Tumor-Associated HLA-II Antigens Mol. Cell. Proteom. 2021 20 100032 10.1074/mcp.RA120.002201 33592498
Zagzag D. Salnikow K. Chiriboga L. Yee H. Lan L. Ali M.A. Garcia R. Demaria S. Newcomb E.W. Downregulation of Major Histocompatibility Complex Antigens in Invading Glioma Cells: Stealth Invasion of the Brain Lab. Investig. 2005 85 328 341 10.1038/labinvest.3700233 15716863
Kanaseki T. Ikeda H. Takamura Y. Toyota M. Hirohashi Y. Tokino T. Himi T. Sato N. Histone Deacetylation, But Not Hypermethylation, Modifies Class II Transactivator and MHC Class II Gene Expression in Squamous Cell Carcinomas J. Immunol. 2003 170 4980 4985 10.4049/jimmunol.170.10.4980 12734341
Morris A.C. Spangler W.E. Boss J.M. Methylation of Class II Trans-Activator Promoter IV: A Novel Mechanism of MHC Class II Gene Control J. Immunol. 2000 164 4143 4149 10.4049/jimmunol.164.8.4143 10754309
Takamura Y. Ikeda H. Kanaseki T. Toyota M. Tokino T. Imai K. Houkin K. Sato N. Regulation of MHC Class II Expression in Glioma Cells by Class II Transactivator (CIITA) Glia 2004 45 392 405 10.1002/glia.10343 14966870
van der Stoep N. Biesta P. Quinten E. van den Elsen P.J. Lack of IFN-Gamma-Mediated Induction of the Class II Transactivator (CIITA) through Promoter Methylation Is Predominantly Found in Developmental Tumor Cell Lines Int. J. Cancer 2002 97 501 507 10.1002/ijc.1623
Soos J.M. Krieger J.I. Stüve O. King C.L. Patarroyo J.C. Aldape K. Wosik K. Slavin A.J. Nelson P.A. Antel J.P. et al. Malignant Glioma Cells Use MHC Class II Transactivator (CIITA) Promoters III and IV to Direct IFN-γ-Inducible CIITA Expression and Can Function as Nonprofessional Antigen Presenting Cells in Endocytic Processing and CD4+ T-Cell Activation Glia 2001 36 391 405 10.1002/glia.1125
Bou Nasser Eddine F. Forlani G. Lombardo L. Tedeschi A. Tosi G. Accolla R.S. CIITA-Driven MHC Class II Expressing Tumor Cells Can Efficiently Prime Naive CD4+ TH Cells in Vivo and Vaccinate the Host against Parental MHC-II-Negative Tumor Cells Oncoimmunology 2017 6 e1261777 10.1080/2162402X.2016.1261777
Meazza R. Comes A. Orengo A.M. Ferrini S. Accolla R.S. Tumor Rejection by Gene Transfer of the MHC Class II Transactivator in Murine Mammary Adenocarcinoma Cells Eur. J. Immunol. 2003 33 1183 1192 10.1002/eji.200323712 12731043
Celesti F. Gatta A. Shallak M. Chiaravalli A.M. Cerati M. Sessa F. Accolla R.S. Forlani G. Protective Anti-Tumor Vaccination against Glioblastoma Expressing the MHC Class II Transactivator CIITA Front. Immunol. 2023 14 1133177 10.3389/fimmu.2023.1133177 36993983
Szatmari T. Lumniczky K. Desaknai S. Trajcevski S. Hidvegi E.J. Hamada H. Safrany G. Detailed Characterization of the Mouse Glioma 261 Tumor Model for Experimental Glioblastoma Therapy Cancer Sci. 2006 97 546 553 10.1111/j.1349-7006.2006.00208.x 16734735
Ekkirala C.R. Cappello P. Accolla R.S. Giovarelli M. Romero I. Garrido C. Garcia-Lora A.M. Novelli F. Class II Transactivator-Induced MHC Class II Expression in Pancreatic Cancer Cells Leads to Tumor Rejection and a Specific Antitumor Memory Response Pancreas 2014 43 1066 1072 10.1097/MPA.0000000000000160 24987872
Artesi M. Kroonen J. Bredel M. Nguyen-Khac M. Deprez M. Schoysman L. Poulet C. Chakravarti A. Kim H. Scholtens D. et al. Connexin 30 Expression Inhibits Growth of Human Malignant Gliomas but Protects Them against Radiation Therapy Neuro Oncol. 2015 17 392 406 10.1093/neuonc/nou215
Robe P.A. Bentires-Alj M. Bonif M. Rogister B. Deprez M. Haddada H. Khac M.-T.N. Jolois O. Erkmen K. Merville M.-P. et al. In Vitro and In Vivo Activity of the Nuclear Factor-ΚB Inhibitor Sulfasalazine in Human Glioblastomas Clin. Cancer Res. 2004 10 5595 5603 10.1158/1078-0432.CCR-03-0392
Sneeboer M.A.M. Snijders G.J.L.J. Berdowski W.M. Fernández-Andreu A. van Mierlo H.C. Berdenis van Berlekom A. Litjens M. Kahn R.S. Hol E.M. de Witte L.D. Microglia in Post-Mortem Brain Tissue of Patients with Bipolar Disorder Are Not Immune Activated Transl. Psychiatry 2019 9 153 10.1038/s41398-019-0490-x
Klingemann H.-G. Martinson J. Ex Vivo Expansion of Natural Killer Cells for Clinical Applications Cytotherapy 2004 6 15 22 10.1080/14653240310004548
Ausman J. Shapiro W. Rall D. Studies on the chemotherapy of experimental brain tumors: Development of an experimental model Studies on the Chemotherapy of Experimental Brain Tumors: Development of an Experimental Model Cancer Res. 1970 30 2394 2400
Oh T. Fakurnejad S. Sayegh E.T. Clark A.J. Ivan M.E. Sun M.Z. Safaee M. Bloch O. James C.D. Parsa A.T. Immunocompetent Murine Models for the Study of Glioblastoma Immunotherapy J. Transl. Med. 2014 12 107 10.1186/1479-5876-12-107
Huang H. Georganaki M. Conze L.L. Laviña B. van Hooren L. Vemuri K. van de Walle T. Ramachandran M. Zhang L. Pontén F. et al. ELTD1 Deletion Reduces Vascular Abnormality and Improves T-Cell Recruitment after PD-1 Blockade in Glioma Neuro Oncol. 2022 24 398 411 10.1093/neuonc/noab181 34347079
Kollis P.M. Ebert L.M. Toubia J. Bastow C.R. Ormsby R.J. Poonnoose S.I. Lenin S. Tea M.N. Pitson S.M. Gomez G.A. et al. Characterising Distinct Migratory Profiles of Infiltrating T-Cell Subsets in Human Glioblastoma Front. Immunol. 2022 13 850226 10.3389/fimmu.2022.850226 35464424
Sackstein R. Schatton T. Barthel S.R. T-Lymphocyte Homing: An Underappreciated yet Critical Hurdle for Successful Cancer Immunotherapy Lab. Investig. 2017 97 669 697 10.1038/labinvest.2017.25 28346400
Golán I. Rodríguez de la Fuente L. Costoya J. NK Cell-Based Glioblastoma Immunotherapy Cancers 2018 10 522 10.3390/cancers10120522 30567306
Lee S.J. Kang W.Y. Yoon Y. Jin J.Y. Song H.J. Her J.H. Kang S.M. Hwang Y.K. Kang K.J. Joo K.M. et al. Natural Killer (NK) Cells Inhibit Systemic Metastasis of Glioblastoma Cells and Have Therapeutic Effects against Glioblastomas in the Brain BMC Cancer 2015 15 1011 10.1186/s12885-015-2034-y
Felices M. Lenvik A.J. McElmurry R. Chu S. Hinderlie P. Bendzick L. Geller M.A. Tolar J. Blazar B.R. Miller J.S. Continuous Treatment with IL-15 Exhausts Human NK Cells via a Metabolic Defect J. Clin. Investig. 2018 3 e96219 10.1172/jci.insight.96219
Shaim H. Shanley M. Basar R. Daher M. Gumin J. Zamler D.B. Uprety N. Wang F. Huang Y. Gabrusiewicz K. et al. Targeting the Av Integrin/TGF-β Axis Improves Natural Killer Cell Function against Glioblastoma Stem Cells J. Clin. Investig. 2021 131 e142116 10.1172/JCI142116
Puigdelloses M. Garcia-Moure M. Labiano S. Laspidea V. Gonzalez-Huarriz M. Zalacain M. Marrodan L. Martinez-Velez N. De la Nava D. Ausejo I. et al. CD137 and PD-L1 Targeting with Immunovirotherapy Induces a Potent and Durable Antitumor Immune Response in Glioblastoma Models J. Immunother. Cancer 2021 9 e002644 10.1136/jitc-2021-002644
