Preventing vaccinia virus class-I epitopes presentation by HSV-ICP47 enhances the immunogenicity of a TAP-independent cancer vaccine epitope
Nermin Raafat
Department of Biomedicine, Oncology group, Institute of Surgical Research and Hospital Management, University of Basel, Switzerland
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
Search for more papers by this authorCharlotte Sadowski-Cron
Department of Thoracic Surgery, University Hospital of Basel, Switzerland
Search for more papers by this authorChantal Mengus
Department of Biomedicine, Oncology group, Institute of Surgical Research and Hospital Management, University of Basel, Switzerland
Search for more papers by this authorMichael Heberer
Department of Biomedicine, Oncology group, Institute of Surgical Research and Hospital Management, University of Basel, Switzerland
Search for more papers by this authorGiulio C. Spagnoli
Department of Biomedicine, Oncology group, Institute of Surgical Research and Hospital Management, University of Basel, Switzerland
Search for more papers by this authorCorresponding Author
Paul Zajac
Department of Biomedicine, Oncology group, Institute of Surgical Research and Hospital Management, University of Basel, Switzerland
Tel.: 0041-0-61-265-2330, Fax: 0041-0-61-265-3990
ICFS, laboratory 404, Hebelstrasse, 20, CH-4031, Basel, SwitzerlandSearch for more papers by this authorNermin Raafat
Department of Biomedicine, Oncology group, Institute of Surgical Research and Hospital Management, University of Basel, Switzerland
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
Search for more papers by this authorCharlotte Sadowski-Cron
Department of Thoracic Surgery, University Hospital of Basel, Switzerland
Search for more papers by this authorChantal Mengus
Department of Biomedicine, Oncology group, Institute of Surgical Research and Hospital Management, University of Basel, Switzerland
Search for more papers by this authorMichael Heberer
Department of Biomedicine, Oncology group, Institute of Surgical Research and Hospital Management, University of Basel, Switzerland
Search for more papers by this authorGiulio C. Spagnoli
Department of Biomedicine, Oncology group, Institute of Surgical Research and Hospital Management, University of Basel, Switzerland
Search for more papers by this authorCorresponding Author
Paul Zajac
Department of Biomedicine, Oncology group, Institute of Surgical Research and Hospital Management, University of Basel, Switzerland
Tel.: 0041-0-61-265-2330, Fax: 0041-0-61-265-3990
ICFS, laboratory 404, Hebelstrasse, 20, CH-4031, Basel, SwitzerlandSearch for more papers by this authorAbstract
Herpes simplex virus protein ICP47, encoded by US12 gene, strongly downregulates major histocompatibility complex (MHC) class-I antigen restricted presentation by blocking transporter associated with antigen processing (TAP) protein. To decrease viral vector antigenic immunodominance and MHC class-I driven clearance, we engineered recombinant vaccinia viruses (rVV) expressing ICP47 alone (rVV-US12) or together with endoplasmic reticulum (ER)-targeted Melan-A/MART-127–35 model tumor epitope (rVV-MUS12). In this study, we show that antigen presenting cells (APC), infected with rVV-US12, display a decreased ability to present TAP dependent MHC class-I restricted viral antigens to CD8+ T-cells. While HLA class-I cell surface expression is strongly downregulated, other important immune related molecules such as CD80, CD44 and, most importantly, MHC class-II are unaffected. Characterization of rVV-MUS12 infected cells demonstrates that over-expression of a TAP-independent peptide, partially compensates for ICP47 induced surface MHC class-I downregulation (30% vs. 70% respectively). Most importantly, in conditions where clearance of infected APC by virus-specific CTL represents a limiting factor, a significant enhancement of CTL responses to the tumor epitope can be detected in cultures stimulated with rVV-MUS12, as compared to those stimulated by rVV-MART alone. Such reagents could become of high relevance in multiple boost protocols required for cancer immunotherapy, to limit vector-specific responsiveness.
Supporting Information
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References
- 1 Neumann L, Kraas W, Uebel S, Jung G, Tampe R. The active domain of the herpes simplex virus protein ICP47: a potent inhibitor of the transporter associated with antigen processing. J Mol Biol 1997; 272: 484–92.
- 2 Fruh K, Ahn K, Djaballah H, Sempe P, van Endert PM, Tampe R, Peterson PA, Yang Y. A viral inhibitor of peptide transporters for antigen presentation. Nature 1995; 375: 415–18.
- 3 Aisenbrey C, Sizun C, Koch J, Herget M, Abele R, Bechinger B, Tampe R. Structure and dynamics of membrane-associated ICP47, a viral inhibitor of the MHC I antigen-processing machinery. J Biol Chem 2006; 281: 30365–72.
- 4 Moss B. Vaccinia virus: a tool for research and vaccine development. Science 1991; 252: 1662–67.
- 5 Guo ZS, Bartlett DL. Vaccinia as a vector for gene delivery. Exp Opin Biol Ther 2004; 4: 901–17.
- 6 Kaufman HL. The role of poxviruses in tumor immunotherapy. Surgery 2003; 134: 731–37.
- 7 Shen Y, Nemunaitis J. Fighting cancer with vaccinia virus: teaching new tricks to an old dog. Mol Ther 2005; 11: 180–95.
- 8 Demkowicz WE, Jr, Littaua RA, Wang J, Ennis FA. Human cytotoxic T-cell memory: long-lived responses to vaccinia virus. J Virol 1996; 70: 2627–31.
- 9 Hsieh SM, Pan SC, Chen SY, Huang PF, Chang SC. Age distribution for T cell reactivity to vaccinia virus in a healthy population. Clin Infect Dis 2004; 38: 86–89.
- 10 Smith CL, Mirza F, Pasquetto V, Tscharke DC, Palmowski MJ, Dunbar PR, Sette A, Harris AL, Cerundolo V. Immunodominance of poxviral-specific CTL in a human trial of recombinant-modified vaccinia Ankara. J Immunol 2005; 175: 8431–37.
- 11 Harrington LE, Most RR, Whitton JL, Ahmed R. Recombinant vaccinia virus-induced T-cell immunity: quantitation of the response to the virus vector and the foreign epitope. J Virol 2002; 76: 3329–37.
- 12 Oertli D, Marti WR, Zajac P, Noppen C, Kocher T, Padovan E, Adamina M, Schumacher R, Harder F, Heberer M, Spagnoli GC. Rapid induction of specific cytotoxic T lymphocytes against melanoma-associated antigens by a recombinant vaccinia virus vector expressing multiple immunodominant epitopes and costimulatory molecules in vivo. Hum Gene Ther 2002; 13: 569–75.
- 13 Zajac P, Schutz A, Oertli D, Noppen C, Schaefer C, Heberer M, Spagnoli GC, Marti WR. Enhanced generation of cytotoxic T lymphocytes using recombinant vaccinia virus expressing human tumor-associated antigens and B7 costimulatory molecules. Cancer Res 1998; 58: 4567–71.
- 14 Zajac P, Oertli D, Marti W, Adamina M, Bolli M, Guller U, Noppen C, Padovan E, Schultz-Thater E, Heberer M, Spagnoli G. Phase I/II clinical trial of a nonreplicative vaccinia virus expressing multiple HLA-A0201-restricted tumor-associated epitopes and costimulatory molecules in metastatic melanoma patients. Hum Gene Ther 2003; 14: 1497–510.
- 15 Adamina M, Rosenthal R, Weber WP, Frey DM, Viehl CT, Bolli M, Huegli RW, Jacob AL, Heberer M, Oertli D, Marti W, Spagnoli GC, et al. Intranodal immunization with a vaccinia virus encoding multiple antigenic epitopes and costimulatory molecules in metastatic melanoma. Mol Ther 2009; 18: 651–59.
- 16 Feder-Mengus C, Schultz-Thater E, Oertli D, Marti WR, Heberer M, Spagnoli GC, Zajac P. Nonreplicating recombinant vaccinia virus expressing CD40 ligand enhances APC capacity to stimulate specific CD4+ and CD8+ T cell responses. Hum Gene Ther 2005; 16: 348–60.
- 17 Davison AJ, Moss B. Structure of vaccinia virus early promoters. J Mol Biol 1989; 210: 749–69.
- 18 Zajac P. Non-replicating recombinant vaccinia virus expressing CD80 to enhance T-cell stimulation. Methods Mol Biol 2009; 514: 151–62.
- 19 Tsung K, Yim JH, Marti W, Buller RM, Norton JA. Gene expression and cytopathic effect of vaccinia virus inactivated by psoralen and long-wave UV light. J Virol 1996; 70: 165–71.
- 20 Anderson K, Cresswell P, Gammon M, Hermes J, Williamson A, Zweerink H. Endogenously synthesized peptide with an endoplasmic reticulum signal sequence sensitizes antigen processing mutant cells to class I-restricted cell-mediated lysis. J Exp Med 1991; 174: 489–92.
- 21 Bacik I, Cox JH, Anderson R, Yewdell JW, Bennink JR. TAP (transporter associated with antigen processing)-independent presentation of endogenously synthesized peptides is enhanced by endoplasmic reticulum insertion sequences located at the amino- but not carboxyl-terminus of the peptide. J Immunol 1994; 152: 381–87.
- 22
Zajac P,
Oertli D,
Spagnoli GC,
Noppen C,
Schaefer C,
Heberer M,
Marti WR.
Generation of tumoricidal cytotoxic T lymphocytes from healthy donors after in vitro stimulation with a replication-incompetent vaccinia virus encoding MART-1/Melan-A 27-35 epitope.
Int J Cancer
1997;
71:
491–96.
10.1002/(SICI)1097-0215(19970502)71:3<491::AID-IJC30>3.0.CO;2-G CAS PubMed Web of Science® Google Scholar
- 23 Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H. The central role of CD4(+) T cells in the antitumor immune response. J Exp Med 1998; 188: 2357–68.
- 24 Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1994; 1: 793–801.
- 25 Termeer C, Averbeck M, Hara H, Eibel H, Herrlich P, Sleeman J, Simon JC. Targeting dendritic cells with CD44 monoclonal antibodies selectively inhibits the proliferation of naive CD4+ T-helper cells by induction of FAS-independent T-cell apoptosis. Immunology 2003; 109: 32–40.
- 26 Drexler I, Staib C, Kastenmuller W, Stevanovic S, Schmidt B, Lemonnier FA, Rammensee HG, Busch DH, Bernhard H, Erfle V, Sutter G. Identification of vaccinia virus epitope-specific HLA-A*0201-restricted T cells and comparative analysis of smallpox vaccines. Proc Natl Acad Sci U S A 2003; 100: 217–22.
- 27 Terajima M, Cruz J, Raines G, Kilpatrick ED, Kennedy JS, Rothman AL, Ennis FA. Quantitation of CD8+ T cell responses to newly identified HLA-A*0201-restricted T cell epitopes conserved among vaccinia and variola (smallpox) viruses. J Exp Med 2003; 197: 927–32.
- 28 Schutz A, Oertli D, Marti WR, Noppen C, Padovan E, Spagnoli GC, Heberer M, Zajac P. Immunogenicity of nonreplicating recombinant vaccinia expressing HLA-A201 targeted or complete MART-1/Melan-A antigen. Cancer Gene Ther 2001; 8: 655–61.
- 29 Kaplan JM, Yu Q, Piraino ST, Pennington SE, Shankara S, Woodworth LA, Roberts BL. Induction of antitumor immunity with dendritic cells transduced with adenovirus vector-encoding endogenous tumor-associated antigens. J Immunol 1999; 163: 699–707.
- 30 Clay TM, Custer MC, McKee MD, Parkhurst M, Robbins PF, Kerstann K, Wunderlich J, Rosenberg SA, Nishimura MI. Changes in the fine specificity of gp100(209-217)-reactive T cells in patients following vaccination with a peptide modified at an HLA-A2.1 anchor residue. J Immunol 1999; 162: 1749–55.
- 31 Hong M, Li WZ, Li QH. [The immune escape mechanism of herpes simplex virus type 1--suppression of transporter associated with antigen processing (TAP) by ICP47]. Bing Du Xue Bao 2007; 23: 72–75.
- 32 Tanaka Y, Anderson RW, Maloy WL, Tevethia SS. Localization of an immunorecessive epitope on SV40 T antigen by H-2Db-restricted cytotoxic T-lymphocyte clones and a synthetic peptide. Virology 1989; 171: 205–13.
- 33 Webby RJ, Andreansky S, Stambas J, Rehg JE, Webster RG, Doherty PC, Turner SJ. Protection and compensation in the influenza virus-specific CD8+ T cell response. Proc Natl Acad Sci U S A 2003; 100: 7235–40.
- 34 Weidt G, Utermohlen O, Heukeshoven J, Lehmann-Grube F, Deppert W. Relationship among immunodominance of single CD8+ T cell epitopes, virus load, and kinetics of primary antiviral CTL response. J Immunol 1998; 160: 2923–31.
- 35 Chambers B, Grufman P, Fredriksson V, Andersson K, Roseboom M, Laban S, Camps M, Wolpert EZ, Wiertz EJ, Offringa R, Ljunggren HG, van HT. Induction of protective CTL immunity against peptide transporter TAP-deficient tumors through dendritic cell vaccination. Cancer Res 2007; 67: 8450–55.
- 36 Lampen MH, Verweij MC, Querido B, van der Burg SH, Wiertz EJ, van HT. CD8+ T Cell Responses against TAP-Inhibited Cells Are Readily Detected in the Human Population. J Immunol 2010; 185: 6508–17.
- 37 van HT, Wolpert EZ, van VP, Laban S, van d, V, Roseboom M, Bres S, Grufman P, de RA, Meiring H, de JA, Franken K et al. Selective cytotoxic T-lymphocyte targeting of tumor immune escape variants. Nat Med 2006; 12: 417–24.
- 38 Mumberg D, Monach PA, Wanderling S, Philip M, Toledano AY, Schreiber RD, Schreiber H. CD4(+) T cells eliminate MHC class II-negative cancer cells in vivo by indirect effects of IFN-gamma. Proc Natl Acad Sci U S A 1999; 96: 8633–38.
- 39 Qin Z and Blankenstein T. CD4+ T cell--mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFN gamma receptor expression by nonhematopoietic cells. Immunity 2000; 12: 677–86.
- 40 Jarahian M, Fiedler M, Cohnen A, Djandji D, Hammerling GJ, Gati C, Cerwenka A, Turner PC, Moyer RW, Watzl C, Hengel H, Momburg F. Modulation of NKp30- and NKp46-mediated natural killer cell responses by poxviral hemagglutinin. PLoS Pathog 2011; 7: e1002195.
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