BACKGROUND/AIM: Glioblastoma (GBM) is one of the deadliest human cancers responding very poorly to therapy. Although the central nervous system has been traditionally considered an immunologically privileged site with an enhanced immune response, GBM appears to benefit from this immunosuppressive milieu. Immunomodulatory molecules play an important role in immune tumor-host interactions. Non-classical human leukocyte antigens (HLA) class Ib molecules HLA-E, HLA-F, and HLA-G have been previously described to be involved in protecting semi-allogeneic fetal allografts from the maternal immune response and in transplant tolerance as well as tumoral immune escape. Unfortunately, their role in GBM remains poorly understood. Our study, therefore, aimed to characterize the relationship between the expression of these molecules in GBM on the transcriptional level and clinicopathological and molecular features of GBM as well as the effect of ionizing radiation. MATERIALS AND METHODS: We performed the analysis of HLA-E, HLA-F, and HLA-G mRNA expression in 69 GBM tissue samples and 21 non-tumor brain tissue samples (controls) by reverse transcription polymerase chain reaction. Furthermore, two primary GBM cell cultures had been irradiated to identify the effect of ionizing radiation on the expression of non-classical HLA molecules. RESULTS: Analyses revealed that both HLA-E and HLA-F are significantly up-regulated in GBM samples. Subsequent survival analysis showed a significant association between low expression of HLA-E and shorter survival of GBM patients. The dysregulated expression of both molecules was also observed between patients with methylated and unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter. Finally, we showed that ionizing radiation increased HLA-E expression level in GBM cells in vitro. CONCLUSION: HLA-E and HLA-F play an important role in GBM biology and could be used as diagnostic biomarkers, and in the case of HLA-E also as a prognostic biomarker.

1st Department of Pathology St Anne's University Hospital and Faculty of Medicine of Masaryk University Brno Czech Republic

Central European Institute of Technology Masaryk University Brno Czech Republic

Central European Institute of Technology Masaryk University Brno Czech Republic;

Department of Biology Faculty of Medicine of Masaryk University Brno Czech Republic

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Neurosurgery St Anne's University Hospital and Faculty of Medicine of Masaryk University Brno Czech Republic

Department of Neurosurgery University Hospital Brno Brno Czech Republic

Department of Neurosurgery University Hospital Ostrava Ostrava Czech Republic

Department of Pathology University Hospital Brno Brno Czech Republic

Department of Pathology University Hospital Brno Brno Czech Republic;

Department of Radiation Oncology Masaryk Memorial Cancer Institute and Faculty of Medicine of Masaryk University Brno Czech Republic

Zobrazit více v PubMed

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups , National Cancer Institute of Canada Clinical Trials Group Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–996. doi: 10.1056/NEJMoa043330. PubMed DOI

Tan AC, Ashley DM, López GY, Malinzak M, Friedman HS, Khasraw M. Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 2020;70(4):299–312. doi: 10.3322/caac.21613. PubMed DOI

Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, Di Meco F, Lieberman F, Zhu JJ, Stragliotto G, Tran D, Brem S, Hottinger A, Kirson ED, Lavy-Shahaf G, Weinberg U, Kim CY, Paek SH, Nicholas G, Bruna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017;318(23):2306–2316. doi: 10.1001/jama.2017.18718. PubMed DOI PMC

Johnson DR, O’Neill BP. Glioblastoma survival in the United States before and during the temozolomide era. J Neurooncol. 2012;107(2):359–364. doi: 10.1007/s11060-011-0749-4. PubMed DOI

Pachter JS, de Vries HE, Fabry Z. The blood-brain barrier and its role in immune privilege in the central nervous system. J Neuropathol Exp Neurol. 2003;62(6):593–604. doi: 10.1093/jnen/62.6.593. PubMed DOI

Gallegos CE, Michelin S, Dubner D, Carosella ED. Immunomodulation of classical and non-classical HLA molecules by ionizing radiation. Cell Immunol. 2016;303:16–23. doi: 10.1016/j.cellimm.2016.04.005. PubMed DOI

Balner H. The major histocompatibility complex of primates: evolutionary aspects and comparative histogenetics. Philos Trans R Soc Lond B Biol Sci. 1981;292(1057):109–119. doi: 10.1098/rstb.1981.0019. PubMed DOI

King A, Allan DS, Bowen M, Powis SJ, Joseph S, Verma S, Hiby SE, McMichael AJ, Loke YW, Braud VM. HLA-E is expressed on trophoblast and interacts with CD94/NKG2 receptors on decidual NK cells. Eur J Immunol. 2000;30(6):1623–1631. doi: 10.1002/1521-4141(200006)30:6<1623::AID-IMMU1623>3.0.CO;2-M. PubMed DOI

Kovats S, Main EK, Librach C, Stubblebine M, Fisher SJ, DeMars R. A class I antigen, HLA-G, expressed in human trophoblasts. Science. 1990;248(4952):220–223. doi: 10.1126/science.2326636. PubMed DOI

Ishitani A, Sageshima N, Lee N, Dorofeeva N, Hatake K, Marquardt H, Geraghty DE. Protein expression and peptide binding suggest unique and interacting functional roles for HLA-E, F, and G in maternal-placental immune recognition. J Immunol. 2003;171(3):1376–1384. doi: 10.4049/jimmunol.171.3.1376. PubMed DOI

Wischhusen J, Friese MA, Mittelbronn M, Meyermann R, Weller M. HLA-E protects glioma cells from NKG2D-mediated immune responses in vitro: implications for immune escape in vivo. J Neuropathol Exp Neurol. 2005;64(6):523–528. doi: 10.1093/jnen/64.6.523. PubMed DOI

Romagnani C, Pietra G, Falco M, Millo E, Mazzarino P, Biassoni R, Moretta A, Moretta L, Mingari MC. Identification of HLA-E-specific alloreactive T lymphocytes: a cell subset that undergoes preferential expansion in mixed lymphocyte culture and displays a broad cytolytic activity against allogeneic cells. Proc Natl Acad Sci USA. 2002;99(17):11328–11333. doi: 10.1073/pnas.172369799. PubMed DOI PMC

Braud VM, Allan DS, O’Callaghan CA, Söderström K, D’Andrea A, Ogg GS, Lazetic S, Young NT, Bell JI, Phillips JH, Lanier LL, McMichael AJ. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature. 1998;391(6669):795–799. doi: 10.1038/35869. PubMed DOI

Lee N, Goodlett DR, Ishitani A, Marquardt H, Geraghty DE. HLA-E surface expression depends on binding of TAP-dependent peptides derived from certain HLA class I signal sequences. J Immunol. 1998;160(10):4951–4960. PubMed

Braud VM, Allan DS, Wilson D, McMichael AJ. TAP- and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide. Curr Biol. 1998;8(1):1–10. doi: 10.1016/s0960-9822(98)70014-4. PubMed DOI

Ladasky JJ, Boyle S, Seth M, Li H, Pentcheva T, Abe F, Steinberg SJ, Edidin M. Bap31 enhances the endoplasmic reticulum export and quality control of human class I MHC molecules. J Immunol. 2006;177(9):6172–6181. doi: 10.4049/jimmunol.177.9.6172. PubMed DOI PMC

Sadasivan B, Lehner PJ, Ortmann B, Spies T, Cresswell P. Roles for calreticulin and a novel glycoprotein, tapasin, in the interaction of MHC class I molecules with TAP. Immunity. 1996;5(2):103–114. doi: 10.1016/s1074-7613(00)80487-2. PubMed DOI

Gilfillan S, Ho EL, Cella M, Yokoyama WM, Colonna M. NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation. Nat Immunol. 2002;3(12):1150–1155. doi: 10.1038/ni857. PubMed DOI

Iwaszko M, Bogunia-Kubik K. Clinical significance of the HLA-E and CD94/NKG2 interaction. Arch Immunol Ther Exp (Warsz) 2011;59(5):353–367. doi: 10.1007/s00005-011-0137-y. PubMed DOI

Kaiser BK, Barahmand-Pour F, Paulsene W, Medley S, Geraghty DE, Strong RK. Interactions between NKG2x immunoreceptors and HLA-E ligands display overlapping affinities and thermodynamics. J Immunol. 2005;174(5):2878–2884. doi: 10.4049/jimmunol.174.5.2878. PubMed DOI

Sullivan LC, Clements CS, Rossjohn J, Brooks AG. The major histocompatibility complex class Ib molecule HLA-E at the interface between innate and adaptive immunity. Tissue Antigens. 2008;72(5):415–424. doi: 10.1111/j.1399-0039.2008.01138.x. PubMed DOI

Wainwright SD, Biro PA, Holmes CH. HLA-F is a predominantly empty, intracellular, TAP-associated MHC class Ib protein with a restricted expression pattern. J Immunol. 2000;164(1):319–328. doi: 10.4049/jimmunol.164.1.319. PubMed DOI

Lepin EJ, Bastin JM, Allan DS, Roncador G, Braud VM, Mason DY, van der Merwe PA, McMichael AJ, Bell JI, Powis SH, O’Callaghan CA. Functional characterization of HLA-F and binding of HLA-F tetramers to ILT2 and ILT4 receptors. Eur J Immunol. 2000;30(12):3552–3561. doi: 10.1002/1521-4141(200012)30:12<3552::AID-IMMU3552>3.0.CO;2-L. PubMed DOI

Burian A, Wang KL, Finton KA, Lee N, Ishitani A, Strong RK, Geraghty DE. HLA-F and MHC-I open conformers bind natural killer cell Ig-like receptor KIR3DS1. PLoS One. 2016;11(9):e0163297. doi: 10.1371/journal.pone.0163297. PubMed DOI PMC

Garcia-Beltran WF, Hölzemer A, Martrus G, Chung AW, Pacheco Y, Simoneau CR, Rucevic M, Lamothe-Molina PA, Pertel T, Kim TE, Dugan H, Alter G, Dechanet-Merville J, Jost S, Carrington M, Altfeld M. Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1. Nat Immunol. 2016;17(9):1067–1074. doi: 10.1038/ni.3513. PubMed DOI PMC

Goodridge JP, Burian A, Lee N, Geraghty DE. HLA-F and MHC class I open conformers are ligands for NK cell Ig-like receptors. J Immunol. 2013;191(7):3553–3562. doi: 10.4049/jimmunol.1300081. PubMed DOI PMC

Goodridge JP, Burian A, Lee N, Geraghty DE. HLA-F complex without peptide binds to MHC class I protein in the open conformer form. J Immunol. 2010;184(11):6199–6208. doi: 10.4049/jimmunol.1000078. PubMed DOI PMC

Goodridge JP, Lee N, Burian A, Pyo CW, Tykodi SS, Warren EH, Yee C, Riddell SR, Geraghty DE. HLA-F and MHC-I open conformers cooperate in a MHC-I antigen cross-presentation pathway. J Immunol. 2013;191(4):1567–1577. doi: 10.4049/jimmunol.1300080. PubMed DOI PMC

Goldman-Wohl DS, Ariel I, Greenfield C, Hochner-Celnikier D, Cross J, Fisher S, Yagel S. Lack of human leukocyte antigen-G expression in extravillous trophoblasts is associated with pre-eclampsia. Mol Hum Reprod. 2000;6(1):88–95. doi: 10.1093/molehr/6.1.88. PubMed DOI

Ober C, Aldrich CL, Chervoneva I, Billstrand C, Rahimov F, Gray HL, Hyslop T. Variation in the HLA-G promoter region influences miscarriage rates. Am J Hum Genet. 2003;72(6):1425–1435. doi: 10.1086/375501. PubMed DOI PMC

Goldman-Wohl DS, Ariel I, Greenfield C, Hanoch J, Yagel S. HLA-G expression in extravillous trophoblasts is an intrinsic property of cell differentiation: a lesson learned from ectopic pregnancies. Mol Hum Reprod. 2000;6(6):535–540. doi: 10.1093/molehr/6.6.535. PubMed DOI

Feger U, Tolosa E, Huang YH, Waschbisch A, Biedermann T, Melms A, Wiendl H. HLA-G expression defines a novel regulatory T-cell subset present in human peripheral blood and sites of inflammation. Blood. 2007;110(2):568–577. doi: 10.1182/blood-2006-11-057125. PubMed DOI

Nasef A, Mathieu N, Chapel A, Frick J, François S, Mazurier C, Boutarfa A, Bouchet S, Gorin NC, Thierry D, Fouillard L. Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation. 2007;84(2):231–237. doi: 10.1097/01.tp.0000267918.07906.08. PubMed DOI

Le Discorde M, Moreau P, Sabatier P, Legeais JM, Carosella ED. Expression of HLA-G in human cornea, an immune-privileged tissue. Hum Immunol. 2003;64(11):1039–1044. doi: 10.1016/j.humimm.2003.08.346. PubMed DOI

Chen X, Sun N, Li R, Sang X, Li X, Zhao J, Han J, Yang J, Ikezoe T. Targeting HLA-F suppresses the proliferation of glioma cells via a reduction in hexokinase 2-dependent glycolysis. Int J Biol Sci. 2021;17(5):1263–1276. doi: 10.7150/ijbs.56357. PubMed DOI PMC

Kren L, Slaby O, Muckova K, Lzicarova E, Sova M, Vybihal V, Svoboda T, Fadrus P, Lakomy R, Vanhara P, Krenova Z, Sterba J, Smrcka M, Michalek J. Expression of immune-modulatory molecules HLA-G and HLA-E by tumor cells in glioblastomas: an unexpected prognostic significance. Neuropathology. 2011;31(2):129–134. doi: 10.1111/j.1440-1789.2010.01149.x. PubMed DOI

Lin A, Zhang X, Ruan YY, Wang Q, Zhou WJ, Yan WH. HLA-F expression is a prognostic factor in patients with non-small-cell lung cancer. Lung Cancer. 2011;74(3):504–509. doi: 10.1016/j.lungcan.2011.04.006. PubMed DOI

Seliger B, Jasinski-Bergner S, Quandt D, Stoehr C, Bukur J, Wach S, Legal W, Taubert H, Wullich B, Hartmann A. HLA-E expression and its clinical relevance in human renal cell carcinoma. Oncotarget. 2016;7(41):67360–67372. doi: 10.18632/oncotarget.11744. PubMed DOI PMC

Wu Z, Liang J, Wang Z, Li A, Fan X, Jiang T. HLA-E expression in diffuse glioma: relationship with clinicopathological features and patient survival. BMC Neurol. 2020;20(1):59. doi: 10.1186/s12883-020-01640-4. PubMed DOI PMC

Zhen ZJ, Ling JY, Cai Y, Luo WB, He YJ. Impact of HLA-E gene polymorphism on HLA-E expression in tumor cells and prognosis in patients with stage III colorectal cancer. Med Oncol. 2013;30(1):482. doi: 10.1007/s12032-013-0482-2. PubMed DOI

Feng E, Liang T, Wang X, Du J, Tang K, Wang X, Wang F, You G. Correlation of alteration of HLA-F expression and clinical characterization in 593 brain glioma samples. J Neuroinflammation. 2019;16(1):33. doi: 10.1186/s12974-019-1418-3. PubMed DOI PMC

Tang J, Shao W, Dorak MT, Li Y, Miike R, Lobashevsky E, Wiencke JK, Wrensch M, Kaslow RA, Cobbs CS. Positive and negative associations of human leukocyte antigen variants with the onset and prognosis of adult glioblastoma multiforme. Cancer Epidemiol Biomarkers Prev. 2005;14(8):2040–2044. doi: 10.1158/1055-9965.EPI-05-0136. PubMed DOI

Wastowski IJ, Simões RT, Yaghi L, Donadi EA, Pancoto JT, Poras I, Lechapt-Zalcman E, Bernaudin M, Valable S, Carlotti CG Jr, Flajollet S, Jensen SS, Ferrone S, Carosella ED, Kristensen BW, Moreau P. Human leukocyte antigen-G is frequently expressed in glioblastoma and may be induced in vitro by combined 5-aza-2’-deoxycytidine and interferon-γ treatments: results from a multicentric study. Am J Pathol. 2013;182(2):540–552. doi: 10.1016/j.ajpath.2012.10.021. PubMed DOI PMC

Ondracek J, Fadrus P, Sana J, Besse A, Loja T, Vecera M, Radova L, Smrcka M, Slampa P, Slaby O. Global MicroRNA expression profiling identifies unique microRNA pattern of radioresistant glioblastoma cells. Anticancer Res. 2017;37(3):1099–1104. doi: 10.21873/anticanres.11422. PubMed DOI

Hackmon R, Pinnaduwage L, Zhang J, Lye SJ, Geraghty DE, Dunk CE. Definitive class I human leukocyte antigen expression in gestational placentation: HLA-F, HLA-E, HLA-C, and HLAG in extravillous trophoblast invasion on placentation, pregnancy, and parturition. Am J Reprod Immunol. 2017;77(6) doi: 10.1111/aji.12643. PubMed DOI

Coupel S, Moreau A, Hamidou M, Horejsi V, Soulillou JP, Charreau B. Expression and release of soluble HLA-E is an immunoregulatory feature of endothelial cell activation. Blood. 2007;109(7):2806–2814. doi: 10.1182/blood-2006-06-030213. PubMed DOI

Carosella ED, Moreau P, Le Maoult J, Le Discorde M, Dausset J, Rouas-Freiss N. HLA-G molecules: from maternal-fetal tolerance to tissue acceptance. Adv Immunol. 2003;81:199–252. doi: 10.1016/s0065-2776(03)81006-4. PubMed DOI

Lee N, Geraghty DE. HLA-F surface expression on B cell and monocyte cell lines is partially independent from tapasin and completely independent from TAP. J Immunol. 2003;171(10):5264–5271. doi: 10.4049/jimmunol.171.10.5264. PubMed DOI

Wei XH, Orr HT. Differential expression of HLA-E, HLA-F, and HLA-G transcripts in human tissue. Hum Immunol. 1990;29(2):131–142. doi: 10.1016/0198-8859(90)90076-2. PubMed DOI

Derré L, Corvaisier M, Charreau B, Moreau A, Godefroy E, Moreau-Aubry A, Jotereau F, Gervois N. Expression and release of HLA-E by melanoma cells and melanocytes: potential impact on the response of cytotoxic effector cells. J Immunol. 2006;177(5):3100–3107. doi: 10.4049/jimmunol.177.5.3100. PubMed DOI

Harada A, Ishigami S, Kijima Y, Nakajo A, Arigami T, Kurahara H, Kita Y, Yoshinaka H, Natsugoe S. Clinical implication of human leukocyte antigen (HLA)-F expression in breast cancer. Pathol Int. 2015;65(11):569–574. doi: 10.1111/pin.12343. PubMed DOI

Wu B, Yang H, Ying S, Lu H, Wang W, Lv J, Xiong H, Hu W. High HLA-F expression is a poor prognosis factor in patients with nasopharyngeal carcinoma. Anal Cell Pathol (Amst) 2018;2018:7691704. doi: 10.1155/2018/7691704. PubMed DOI PMC

Marín R, Ruiz-Cabello F, Pedrinaci S, Méndez R, Jiménez P, Geraghty DE, Garrido F. Analysis of HLA-E expression in human tumors. Immunogenetics. 2003;54(11):767–775. doi: 10.1007/s00251-002-0526-9. PubMed DOI

Andersson E, Poschke I, Villabona L, Carlson JW, Lundqvist A, Kiessling R, Seliger B, Masucci GV. Non-classical HLA-class I expression in serous ovarian carcinoma: Correlation with the HLA-genotype, tumor infiltrating immune cells and prognosis. Oncoimmunology. 2015;5(1):e1052213. doi: 10.1080/2162402X.2015.1052213. PubMed DOI PMC

Boujelbene N, Ben Yahia H, Babay W, Gadria S, Zemni I, Azaiez H, Dhouioui S, Zidi N, Mchiri R, Mrad K, Ouzari HI, Charfi L, Zidi I. HLA-G, HLA-E, and IDO overexpression predicts a worse survival of Tunisian patients with vulvar squamous cell carcinoma. HLA. 2019;94(1):11–24. doi: 10.1111/tan.13536. PubMed DOI

Ishigami S, Arigami T, Okumura H, Uchikado Y, Kita Y, Kurahara H, Maemura K, Kijima Y, Ishihara Y, Sasaki K, Uenosono Y, Natsugoe S. Human leukocyte antigen (HLA)-E and HLA-F expression in gastric cancer. Anticancer Res. 2015;35(4):2279–2285. PubMed

Reimers MS, Engels CC, Putter H, Morreau H, Liefers GJ, van de Velde CJ, Kuppen PJ. Prognostic value of HLA class I, HLA-E, HLA-G and Tregs in rectal cancer: a retrospective cohort study. BMC Cancer. 2014;14:486. doi: 10.1186/1471-2407-14-486. PubMed DOI PMC

Mittelbronn M, Simon P, Löffler C, Capper D, Bunz B, Harter P, Schlaszus H, Schleich A, Tabatabai G, Goeppert B, Meyermann R, Weller M, Wischhusen J. Elevated HLA-E levels in human glioblastomas but not in grade I to III astrocytomas correlate with infiltrating CD8+ cells. J Neuroimmunol. 2007;189(1-2):50–58. doi: 10.1016/j.jneuroim.2007.07.002. PubMed DOI

Spaans VM, Peters AA, Fleuren GJ, Jordanova ES. HLA-E expression in cervical adenocarcinomas: association with improved long-term survival. J Transl Med. 2012;10:184. doi: 10.1186/1479-5876-10-184. PubMed DOI PMC

Levy EM, Bianchini M, Von Euw EM, Barrio MM, Bravo AI, Furman D, Domenichini E, Macagno C, Pinsky V, Zucchini C, Valvassori L, Mordoh J. Human leukocyte antigen-E protein is overexpressed in primary human colorectal cancer. Int J Oncol. 2008;32(3):633–641. PubMed

van Hall T, André P, Horowitz A, Ruan DF, Borst L, Zerbib R, Narni-Mancinelli E, van der Burg SH, Vivier E. Monalizumab: inhibiting the novel immune checkpoint NKG2A. J Immunother Cancer. 2019;7(1):263. doi: 10.1186/s40425-019-0761-3. PubMed DOI PMC

Sun C, Xu J, Huang Q, Huang M, Wen H, Zhang C, Wang J, Song J, Zheng M, Sun H, Wei H, Xiao W, Sun R, Tian Z. High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer. Oncoimmunology. 2016;6(1):e1264562. doi: 10.1080/2162402X.2016.1264562. PubMed DOI PMC

de Kruijf EM, Sajet A, van Nes JG, Natanov R, Putter H, Smit VT, Liefers GJ, van den Elsen PJ, van de Velde CJ, Kuppen PJ. HLA-E and HLA-G expression in classical HLA class I-negative tumors is of prognostic value for clinical outcome of early breast cancer patients. J Immunol. 2010;185(12):7452–7459. doi: 10.4049/jimmunol.1002629. PubMed DOI

Benevolo M, Mottolese M, Tremante E, Rollo F, Diodoro MG, Ercolani C, Sperduti I, Lo Monaco E, Cosimelli M, Giacomini P. High expression of HLA-E in colorectal carcinoma is associated with a favorable prognosis. J Transl Med. 2011;9:184. doi: 10.1186/1479-5876-9-184. PubMed DOI PMC

John T, Black MA, Toro TT, Leader D, Gedye CA, Davis ID, Guilford PJ, Cebon JS. Predicting clinical outcome through molecular profiling in stage III melanoma. Clin Cancer Res. 2008;14(16):5173–5180. doi: 10.1158/1078-0432.CCR-07-4170. PubMed DOI

Kamiya T, Seow SV, Wong D, Robinson M, Campana D. Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells. J Clin Invest. 2019;129(5):2094–2106. doi: 10.1172/JCI123955. PubMed DOI PMC

Lauterbach N, Wieten L, Popeijus HE, Voorter CE, Tilanus MG. HLA-E regulates NKG2C+ natural killer cell function through presentation of a restricted peptide repertoire. Hum Immunol. 2015;76(8):578–586. doi: 10.1016/j.humimm.2015.09.003. PubMed DOI

Michaëlsson J, Teixeira de Matos C, Achour A, Lanier LL, Kärre K, Söderström K. A signal peptide derived from hsp60 binds HLA-E and interferes with CD94/NKG2A recognition. J Exp Med. 2002;196(11):1403–1414. doi: 10.1084/jem.20020797. PubMed DOI PMC

Geraghty DE, Wei XH, Orr HT, Koller BH. Human leukocyte antigen F (HLA-F). An expressed HLA gene composed of a class I coding sequence linked to a novel transcribed repetitive element. J Exp Med. 1990;171(1):1–18. doi: 10.1084/jem.171.1.1. PubMed DOI PMC

Boyle LH, Gillingham AK, Munro S, Trowsdale J. Selective export of HLA-F by its cytoplasmic tail. J Immunol. 2006;176(11):6464–6472. doi: 10.4049/jimmunol.176.11.6464. PubMed DOI

Riederer I, Sievert W, Eissner G, Molls M, Multhoff G. Irradiation-induced up-regulation of HLA-E on macrovascular endothelial cells confers protection against killing by activated natural killer cells. PLoS One. 2010;5(12):e15339. doi: 10.1371/journal.pone.0015339. PubMed DOI PMC

Pereira BI, Devine OP, Vukmanovic-Stejic M, Chambers ES, Subramanian P, Patel N, Virasami A, Sebire NJ, Kinsler V, Valdovinos A, LeSaux CJ, Passos JF, Antoniou A, Rustin MHA, Campisi J, Akbar AN. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nat Commun. 2019;10(1):2387. doi: 10.1038/s41467-019-10335-5. PubMed DOI PMC

Michelin S, Gallegos CE, Dubner D, Favier B, Carosella ED. Ionizing radiation modulates the surface expression of human leukocyte antigen-G in a human melanoma cell line. Hum Immunol. 2009;70(12):1010–1015. doi: 10.1016/j.humimm.2009.07.030. PubMed DOI

Abdel-Wahab Z, Dar MM, Hester D, Vervaert C, Gangavalli R, Barber J, Darrow TL, Seigler HF. Effect of irradiation on cytokine production, MHC antigen expression, and vaccine potential of interleukin-2 and interferon-gamma gene-modified melanoma cells. Cell Immunol. 1996;171(2):246–254. doi: 10.1006/cimm.1996.0200. PubMed DOI

Cangemi G, Morandi B, D’Agostino A, Peri C, Conte R, Damonte G, Ferlazzo G, Biassoni R, Melioli G. IFN-alpha mediates the up-regulation of HLA class I on melanoma cells without switching proteasome to immunoproteasome. Int Immunol. 2003;15(12):1415–1421. doi: 10.1093/intimm/dxg140. PubMed DOI

Nguyen S, Beziat V, Dhedin N, Kuentz M, Vernant JP, Debre P, Vieillard V. HLA-E upregulation on IFN-gamma-activated AML blasts impairs CD94/NKG2A-dependent NK cytolysis after haplo-mismatched hematopoietic SCT. Bone Marrow Transplant. 2009;43(9):693–699. doi: 10.1038/bmt.2008.380. PubMed DOI

Wolpert F, Roth P, Lamszus K, Tabatabai G, Weller M, Eisele G. HLA-E contributes to an immune-inhibitory phenotype of glioblastoma stem-like cells. J Neuroimmunol. 2012;250(1-2):27–34. doi: 10.1016/j.jneuroim.2012.05.010. PubMed DOI

Malmberg KJ, Levitsky V, Norell H, de Matos CT, Carlsten M, Schedvins K, Rabbani H, Moretta A, Söderström K, Levitskaya J, Kiessling R. IFN-gamma protects short-term ovarian carcinoma cell lines from CTL lysis via a CD94/NKG2A-dependent mechanism. J Clin Invest. 2002;110(10):1515–1523. doi: 10.1172/JCI15564. PubMed DOI PMC

Gustafson KS, Ginder GD. Interferon-gamma induction of the human leukocyte antigen-E gene is mediated through binding of a complex containing STAT1alpha to a distinct interferon-gamma-responsive element. J Biol Chem. 1996;271(33):20035–20046. doi: 10.1074/jbc.271.33.20035. PubMed DOI

Min W, Pober JS, Johnson DR. Interferon induction of TAP1: the phosphatase SHP-1 regulates crossover between the IFN-alpha/beta and the IFN-gamma signal-transduction pathways. Circ Res. 1998;83(8):815–823. doi: 10.1161/01.res.83.8.815. PubMed DOI

Whitmire JK, Tan JT, Whitton JL. Interferon-gamma acts directly on CD8+ T cells to increase their abundance during virus infection. J Exp Med. 2005;201(7):1053–1059. doi: 10.1084/jem.20041463. PubMed DOI PMC

Bach EA, Aguet M, Schreiber RD. The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol. 1997;15:563–591. doi: 10.1146/annurev.immunol.15.1.563. PubMed DOI

Yu J, Wei M, Becknell B, Trotta R, Liu S, Boyd Z, Jaung MS, Blaser BW, Sun J, Benson DM Jr, Mao H, Yokohama A, Bhatt D, Shen L, Davuluri R, Weinstein M, Marcucci G, Caligiuri MA. Pro- and antiinflammatory cytokine signaling: reciprocal antagonism regulates interferon-gamma production by human natural killer cells. Immunity. 2006;24(5):575–590. doi: 10.1016/j.immuni.2006.03.016. PubMed DOI

Siegel JP. Effects of interferon-gamma on the activation of human T lymphocytes. Cell Immunol. 1988;111(2):461–472. doi: 10.1016/0008-8749(88)90109-8. PubMed DOI

Weigent DA, Stanton GJ, Johnson HM. Interleukin 2 enhances natural killer cell activity through induction of gamma interferon. Infect Immun. 1983;41(3):992–997. doi: 10.1128/iai.41.3.992-997.1983. PubMed DOI PMC

Yang I, Tihan T, Han SJ, Wrensch MR, Wiencke J, Sughrue ME, Parsa AT. CD8+ T-cell infiltrate in newly diagnosed glioblastoma is associated with long-term survival. J Clin Neurosci. 2010;17(11):1381–1385. doi: 10.1016/j.jocn.2010.03.031. PubMed DOI PMC

Kozlowska AK, Tseng HC, Kaur K, Topchyan P, Inagaki A, Bui VT, Kasahara N, Cacalano N, Jewett A. Resistance to cytotoxicity and sustained release of interleukin-6 and interleukin-8 in the presence of decreased interferon-γ after differentiation of glioblastoma by human natural killer cells. Cancer Immunol Immunother. 2016;65(9):1085–1097. doi: 10.1007/s00262-016-1866-x. PubMed DOI PMC

Davidson B, Elstrand MB, McMaster MT, Berner A, Kurman RJ, Risberg B, Trope CG, Shih IeM. HLA-G expression in effusions is a possible marker of tumor susceptibility to chemotherapy in ovarian carcinoma. Gynecol Oncol. 2005;96(1):42–47. doi: 10.1016/j.ygyno.2004.09.049. PubMed DOI