DOI QR코드

DOI QR Code

Reconstructed Adeno-Associated Virus with the Extracellular Domain of Murine PD-1 Induces Antitumor Immunity

  • Elhag, Osama A.O. (Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University) ;
  • Hu, Xiao-Jing (Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University) ;
  • Wen-Ying, Zhang (Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University) ;
  • Li, Xiong (Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University) ;
  • Yuan, Yong-Ze (Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University) ;
  • Deng, Ling-Feng (Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University) ;
  • Liu, De-Li (Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University) ;
  • Liu, Ying-Le (The State Key Laboratory of Virology, College of Life Sciences, Wuhan University) ;
  • Hui, Geng (Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University)
  • Published : 2012.08.31

Abstract

Background: The negative signaling provided by interactions of the co-inhibitory molecule, programmed death-1 (PD-1), and its ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), is a critical mechanism contributing to tumor evasion; blockade of this pathway has been proven to enhance cytotoxic activity and mediate antitumor therapy. Here we evaluated the anti-tumor efficacy of AAV-mediated delivery of the extracellular domain of murine PD-1 (sPD-1) to a tumor site. Material and Methods: An rAAV vector was constructed in which the expression of sPD-1, a known negative regulator of TCR signals, is driven by human cytomegalovirus immediate early promoter (CMV-P), using a triple plasmid transfection system. Tumor-bearing mice were then treated with the AAV/sPD1 construct and expression of sPD-1 in tumor tissues was determined by semi quantitative RT-PCR, and tumor weights and cytotoxic activity of splenocytes were measured. Results: Analysis of tumor homogenates revealed sPD-1 mRNA to be significantly overexpressed in rAAV/sPD-1 treated mice as compared with control levels. Its use for local gene therapy at the inoculation site of H22 hepatoma cells could inhibit tumor growth, also enhancing lysis of tumor cells by lymphocytes stimulated specifically with an antigen. In addition, PD-1 was also found expressed on the surfaces of activated CD8+ T cells. Conclusion: This study confirmed that expression of the soluble extracellular domain of PD-1 molecule could reduce tumor microenvironment inhibitory effects on T cells and enhance cytotoxicity. This suggests that it might be a potential target for development of therapies to augment T-cell responses in patients with malignancies.

Keywords

PD-1;sPD-1;B7H1;gene therapy;tumor immunotherapy

References

  1. Aalbers CJ, Tak PP, Vervoordeldonk MJ (2011). Advancements in adeno-associated viral gene therapy approaches: exploring a new horizon. F1000 Med Rep, 3, 17.
  2. Aguilar LK, Guzik BW, Aguilar-Cordova E (2011). Cytotoxic immunotherapy strategies for cancer: mechanisms and clinical development. J Cell Biochem, 112, 1969-77. https://doi.org/10.1002/jcb.23126
  3. Blank C, Brown I, Peterson AC, et al (2004). PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res, 64, 1140-5. https://doi.org/10.1158/0008-5472.CAN-03-3259
  4. Borghouts C, Kunz C, Groner B (2005). Current strategies for the development of peptide-based anti-cancer therapeutics. J Pept Sci, 11, 713-26. https://doi.org/10.1002/psc.717
  5. Cao S, Cripps A, Wei MQ (2010). New strategies for cancer gene therapy: progress and opportunities. Clin Exp Pharmacol Physiol, 37, 108-14. https://doi.org/10.1111/j.1440-1681.2009.05268.x
  6. Cao Y, Zhang L, Kamimura Y, et al (2011). B7-H1 overexpression regulates epithelial-mesenchymal transition and accelerates carcinogenesis in skin. Cancer Res, 71, 1235-43. https://doi.org/10.1158/0008-5472.CAN-10-2217
  7. Capece D, Verzella D, Fischietti M, Zazzeroni F, Alesse E (2012). Targeting costimulatory molecules to improve antitumor immunity. J Biomed Biotechnol, 2012, 926321.
  8. Cross D, Burmester JK (2006). Gene therapy for cancer treatment: past, present and future. Clin Med Res, 4, 218-27. https://doi.org/10.3121/cmr.4.3.218
  9. Danylesko I, Beider K, Shimoni A, Nagler A (2012). Novel strategies for immunotherapy in multiple myeloma: previous experience and future directions. Clin Dev Immunol, 2012, 753407
  10. Dong H, Chen L (2003). B7-H1 pathway and its role in the evasion of tumor immunity. J Mol Med (Berl), 81, 281-7. https://doi.org/10.1007/s00109-003-0430-2
  11. Dong H, Strome SE, Salomao DR, et al (2002). Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med, 8, 793-800. https://doi.org/10.1038/nm730
  12. Dulgerian LR, Garrido VV, Stempin CC, Cerban FM (2011). Programmed death ligand 2 regulates arginase induction and modifies Trypanosoma cruzi survival in macrophages during murine experimental infection. Immunology, 133, 29-40. https://doi.org/10.1111/j.1365-2567.2011.03406.x
  13. Feng Z, Huang B, Zhang G, Li D, Wang H (2002). Investigation on the effect of peptides mixture from tumor cells inducing anti-tumor specific immune response. Sci China C Life Sci, 45, 361-9. https://doi.org/10.1360/02yc9040
  14. Flies DB, Sandler BJ, Sznol M, Chen L (2011). Blockade of the B7-H1/PD-1 pathway for cancer immunotherapy. Yale J Biol Med, 84, 409-21.
  15. Freeman GJ, Long AJ, Iwai Y, et al (2000). Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med, 192, 1027-34. https://doi.org/10.1084/jem.192.7.1027
  16. Geng H, Zhang GM, Li D, et al (2006). Soluble form of T cell Ig mucin 3 is an inhibitory molecule in T cell-mediated immune response. J Immunol, 176, 1411-20. https://doi.org/10.4049/jimmunol.176.3.1411
  17. He L, Zhang G, He Y, et al (2005). Blockade of B7-H1 with sPD-1 improves immunity against murine hepatocarcinoma. Anticancer Res, 25, 3309-13.
  18. He YF, Zhang GM, Wang XH, et al (2004). Blocking programmed death-1 ligand-PD-1 interactions by local gene therapy results in enhancement of antitumor effect of secondary lymphoid tissue chemokine. J Immunol, 173, 4919-28. https://doi.org/10.4049/jimmunol.173.8.4919
  19. Hofmeyer KA, Jeon H, Zang X (2011). The PD-1/PD-L1 (B7-H1) pathway in chronic infection-induced cytotoxic T lymphocyte exhaustion. J Biomed Biotechnol, 2011, 451694.
  20. Keswani SG, Balaji S, Le L, et al (2012). Pseudotyped AAV Vector-Mediated Gene Transfer in a Human Fetal Trachea Xenograft Model: Implications for In Utero Gene Therapy for Cystic Fibrosis. PLoS One, 7, e43633. https://doi.org/10.1371/journal.pone.0043633
  21. Lee SK, Seo SH, Kim BS, et al (2005). IFN-gamma regulates the expression of B7-H1 in dermal fibroblast cells. J Dermatol Sci, 40, 95-103. https://doi.org/10.1016/j.jdermsci.2005.06.008
  22. Li C, Bowles DE, van Dyke T, Samulski RJ (2005). Adenoassociated virus vectors: potential applications for cancer gene therapy. Cancer Gene Ther, 12, 913-25. https://doi.org/10.1038/sj.cgt.7700876
  23. Paterson AM, Brown KE, Keir ME, et al (2011). The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo. J Immunol, 187, 1097-105. https://doi.org/10.4049/jimmunol.1003496
  24. Phan GQ, Yang JC, Sherry RM, et al (2003). Cancer regression and autoimmunity induced by cytotoxic T lymphocyteassociated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA, 100, 8372-7. https://doi.org/10.1073/pnas.1533209100
  25. Ponnazhagan S, Mahendra G, Kumar S, et al (2004). Adenoassociated virus 2-mediated antiangiogenic cancer gene therapy: long-term efficacy of a vector encoding angiostatin and endostatin over vectors encoding a single factor. Cancer Res, 64, 1781-7. https://doi.org/10.1158/0008-5472.CAN-03-1786
  26. Qian C, Drozdzik M, Caselmann WH, Prieto J (2000). The potential of gene therapy in the treatment of hepatocellular carcinoma. J Hepatol, 32, 344-51. https://doi.org/10.1016/S0168-8278(00)80082-3
  27. Qian C, Prieto J (2004). Gene therapy of cancer: induction of anti-tumor immunity. Cell Mol Immunol, 1, 105-11.
  28. Qiu H, Liu S, Xie C, Long J, Feng Z (2009). Regulating immunity and inhibiting tumor growth by the recombinant peptide sPD-1-CH50. Anticancer Res, 29, 5089-94.
  29. Rosenberg SA (2001). Progress in human tumour immunology and immunotherapy. Nature, 411, 380-4. https://doi.org/10.1038/35077246
  30. Rozali EN, Hato SV, Robinson BW, Lake RA, Lesterhuis WJ (2012). Programmed death ligand 2 in cancer-induced immune suppression. Clin Dev Immunol, 2012, 656340.
  31. Sangro B, Qian C, Schmitz V, Prieto J (2002). Gene therapy of hepatocellular carcinoma and gastrointestinal tumors. Ann N Y Acad Sci, 963, 6-12.
  32. Streck CJ, Dickson PV, Ng CY, et al (2006). Antitumor efficacy of AAV-mediated systemic delivery of interferon-beta. Cancer Gene Ther, 13, 99-106. https://doi.org/10.1038/sj.cgt.7700878
  33. Topfer K, Kempe S, Muller N, et al (2011). Tumor evasion from T cell surveillance. J Biomed Biotechnol, 2011, 918471.
  34. Wiendl H, Mitsdoerffer M, Hofmeister V, et al (2002). A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape. J Immunol, 168, 4772-80. https://doi.org/10.4049/jimmunol.168.9.4772
  35. Wong RM, Scotland RR, Lau RL, et al (2007). Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs. Int Immunol, 19, 1223-34. https://doi.org/10.1093/intimm/dxm091
  36. Xiao H, Huang B, Yuan Y, et al (2007). Soluble PD-1 facilitates 4-1BBL-triggered antitumor immunity against murine H22 hepatocarcinoma in vivo. Clin Cancer Res, 13, 1823-30. https://doi.org/10.1158/1078-0432.CCR-06-2154
  37. Xing YN, Liang HW, Zhao L, Xu HM (2011). The antitumor activity of exogenous and endogenous canstatin on colorectal cancer cells. Asian Pac J Cancer Prev, 12, 2713-6.
  38. Xu L, Liu Y, He X (2006). Expression and purification of soluble human programmed death-1 in Escherichia coli. Cell Mol Immunol, 3, 139-43
  39. Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, et al (2012). Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med, 209, 1201-17. https://doi.org/10.1084/jem.20112741
  40. Youngnak P, Kozono Y, Kozono H, et al (2003). Differential binding properties of B7-H1 and B7-DC to programmed death-1. Biochem Biophys Res Commun, 307, 672-7. https://doi.org/10.1016/S0006-291X(03)01257-9
  41. Zacchigna S, Zentilin L, Morini M, et al (2004). AAV-mediated gene transfer of tissue inhibitor of metalloproteinases-1 inhibits vascular tumor growth and angiogenesis in vivo. Cancer Gene Ther, 11, 73-80. https://doi.org/10.1038/sj.cgt.7700657
  42. Zeng Z, Shi F, Zhou L, et al (2011). Upregulation of circulating PD-L1/PD-1 is associated with poor post-cryoablation prognosis in patients with HBV-related hepatocellular carcinoma. PLoS One, 6, e23621. https://doi.org/10.1371/journal.pone.0023621

Cited by

  1. IL-12 Regulates B7-H1 Expression in Ovarian Cancer-associated Macrophages by Effects on NF-κB Signalling vol.15, pp.14, 2014, https://doi.org/10.7314/APJCP.2014.15.14.5767
  2. Effect of TLR4 and B7-H1 on Immune Escape of Urothelial Bladder Cancer and its Clinical Significance vol.15, pp.3, 2014, https://doi.org/10.7314/APJCP.2014.15.3.1321
  3. Progresses and Perspectives of Anti-PD-1/PD-L1 Antibody Therapy in Head and Neck Cancers vol.8, pp.2234-943X, 2018, https://doi.org/10.3389/fonc.2018.00563
  4. Soluble immune checkpoints in cancer: production, function and biological significance vol.6, pp.1, 2018, https://doi.org/10.1186/s40425-018-0449-0
  5. PD-1 in human NK cells: evidence of cytoplasmic mRNA and protein expression vol.8, pp.3, 2019, https://doi.org/10.1080/2162402X.2018.1557030