The inhibitor of apoptosis proteins antagonist Debio 1143 promotes the PD-1 blockade-mediated HIV load reduction in blood and tissues of humanized mice


Autoři: Michael Bobardt aff001;  Joseph Kuo aff001;  Udayan Chatterji aff001;  Norbert Wiedemann aff002;  Gregoire Vuagniaux aff002;  Philippe Gallay aff001
Působiště autorů: Department of Immunology & Microbiology, The Scripps Research Institute, La Jolla, California, United States of America aff001;  Debiopharm International S.A., Lausanne, Switzerland aff002
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227715

Souhrn

The immune checkpoint programmed cell death protein 1 (PD-1) plays a major role in T cell exhaustion in cancer and chronic HIV infection. The inhibitor of apoptosis protein antagonist Debio 1143 (D1143) enhances tumor cell death and synergizes with anti-PD-1 agents to promote tumor immunity and displayed HIV latency reversal activity in vitro. We asked in this study whether D1143 would stimulate the potency of an anti-human PD-1 monoclonal antibody (mAb) to reduce HIV loads in humanized mice. Anti-PD-1 mAb treatment decreased PD-1+ CD8+ cell population by 32.3% after interruption of four weeks treatment, and D1143 co-treatment further reduced it from 32.3 to 73%. Anti-PD-1 mAb administration reduced HIV load in blood by 94%, and addition of D1143 further enhanced this reduction from 94 to 97%. D1143 also more profoundly promoted with the anti-PD-1-mediated reduction of HIV loads in all tissues analyzed including spleen (71 to 96.4%), lymph nodes (64.3 to 80%), liver (64.2 to 94.4), lung (64.3 to 80.1%) and thymic organoid (78.2 to 98.2%), achieving a >5 log reduction of HIV loads in CD4+ cells isolated from tissues 2 weeks after drug treatment interruption. Ex vivo anti-CD3/CD28 stimulation increased the ability to activate exhausted CD8+ T cells in infected mice having received in vivo anti-PD-1 treatment by 7.9-fold (5 to 39.6%), and an additional increase by 1.7-fold upon D1143 co-treatment (39.6 to 67.3%). These findings demonstrate for the first time that an inhibitor of apoptosis protein antagonist enhances in a statistically manner the effects of an immune check point inhibitor on antiviral immunity and on HIV load reduction in tissues of humanized mice, suggesting that the combination of two distinct classes of immunomodulatory agents constitutes a promising anti-HIV immunotherapeutic approach.

Klíčová slova:

Apoptosis – Blood – Cytotoxic T cells – HIV – HIV infections – Mouse models – T cells – Viral load


Zdroje

1. UNAIDS (2016) UNAIDS 2016 Global Fact Sheet.

2. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol. 1994; 68: 6103–6110. 8057491

3. Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol. 1994; 68: 4650–4655. 8207839

4. Pantaleo G, Demarest JF, Soudeyns H, Graziosi C, Denis F, Adelsberger JW, et al. Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature. 1994; 370: 463–467. doi: 10.1038/370463a0 8047166

5. Walker CM, Moody DJ, Stites DP, Levy JA. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science. 1986; 234: 1563–1566. doi: 10.1126/science.2431484 2431484

6. Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science. 1999; 283: 857–860. doi: 10.1126/science.283.5403.857 9933172

7. Yang OO, Kalams SA, Rosenzweig M, Trocha A, Jones N, Koziel M, et al. Efficient lysis of human immunodeficiency virus type 1-infected cells by cytotoxic T lymphocytes. J Virol. 1996; 70: 5799–5806. 8709196

8. Yang OO, Garcia-Zepeda EA, Walker BD, Luster AD. Monocyte chemoattractant protein-2 (CC chemokine ligand 8) inhibits replication of human immunodeficiency virus type 1 via CC chemokine receptor 5. J Infect Dis. 2002; 185: 1174–1178. doi: 10.1086/339678 11930329

9. Yang OO, Swanberg SL, Lu Z, Dziejman M, McCoy J, Luster AD, et al. (1999) Enhanced inhibition of human immunodeficiency virus type 1 by Met-stromal-derived factor 1beta correlates with down-modulation of CXCR4. J Virol 73: 4582–4589. 10233917

10. Wagner L, Yang OO, Garcia-Zepeda EA, Ge Y, Kalams SA, Walker BD, et al. Beta chemokines are released from HIV-1-specific cytolytic T-cell granules complexed to proteoglycans. Nature. 1998; 391: 908–911. doi: 10.1038/36129 9495345

11. Yang OO, Kalams SA, Trocha A, Cao H, Luster A, Johnson RP, et al. Suppression of human immunodeficiency virus type 1 replication by CD8+ cells: evidence for HLA class I-restricted triggering of cytolytic and noncytolytic mechanisms. J Virol. 1997; 71: 3120–3128. 9060675

12. Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P, et al. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV suppressive factors produced by CD8+ T cells. Science. 1995; 270: 1811–1815. doi: 10.1126/science.270.5243.1811 8525373

13. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, et al. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med. 1998; 188: 2205–2213. doi: 10.1084/jem.188.12.2205 9858507

14. Wherry EJ, Ahmed R. Memory CD8 T-cell differentiation during viral infection. J Virol. 2004; 78: 5535–5545. doi: 10.1128/JVI.78.11.5535-5545.2004 15140950

15. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006; 439: 682–687. doi: 10.1038/nature04444 16382236

16. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006; 443: 350–354. doi: 10.1038/nature05115 16921384

17. Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, Adams WC, et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med. 2006; 203: 2281–2292. doi: 10.1084/jem.20061496 16954372

18. Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med. 2006; 12: 1198–1202. doi: 10.1038/nm1482 16917489

19. Velu V, Titanji K, Zhu B, Husain S, Pladevega A, Lai L, et al. Enhancing SIV specific immunity in vivo by PD-1 blockade. Nature. 2009; 458: 206–210. doi: 10.1038/nature07662 19078956

20. Dyck L, Mills KHG. Immune checkpoints and their inhibition in cancer and infectious diseases. Eur J Immunol. 2017; 47(5):765–779. doi: 10.1002/eji.201646875 28393361

21. Rao M, Valentini D, Dodoo E, Zumla A, Maeurer M. Anti-PD-1/PD-L1 therapy for infectious diseases: learning from the cancer paradigm. Int J Infect Dis. 2017; 56:221–228. doi: 10.1016/j.ijid.2017.01.028 28163164

22. Kulpa DA, Lawani M, Cooper A, Peretz Y, Ahlers J, Sékaly RP. PD-1 coinhibitory signals: the link between pathogenesis and protection. Semin Immunol. 2013; 25(3):219–27. doi: 10.1016/j.smim.2013.02.002 23548749

23. Porichis F, Kaufmann DE. Role of PD-1 in HIV pathogenesis and as target for therapy. Curr HIV/AIDS Rep. 2012; 9(1):81–90. doi: 10.1007/s11904-011-0106-4 22198819

24. Sakthivel P, Gereke M, Bruder D. Therapeutic intervention in cancer and chronic viral infections: antibody mediated manipulation of PD-1/PD-L1 interaction. Rev Recent Clin Trials. 2012; 7(1):10–23. doi: 10.2174/157488712799363262 22023178

25. Kaufmann DE, Walker BD. PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention. J Immunol. 2009; 182(10):5891–5897. doi: 10.4049/jimmunol.0803771 19414738

26. Hoffmann M, Pantazis N, Martin GE, Hickling S, Hurst J, Meyerowitz J, et al. Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection. PLoS Pathog. 2016; 12(7):e1005661. doi: 10.1371/journal.ppat.1005661 27415828

27. Hurst J, Hoffmann M, Pace M, Williams JP, Thornhill J, Hamlyn E, et al. 2015. Immunological biomarkers predict HIV-1 viral rebound after treatment interruption. Nat Commun. 6:8495. doi: 10.1038/ncomms9495 26449164

28. Breton G, Chomont N, Takata H, Fromentin R, Ahlers J, Filali-Mouhim A, et al. Programmed death-1 is a marker for abnormal distribution of naive/memory T cell subsets in HIV-1 infection. J Immunol. 2013; 191(5):2194–204. doi: 10.4049/jimmunol.1200646 23918986

29. Wei F, Zhong S, Ma Z, Kong H, Medvec A, Ahmed R, et al. Strength of PD-1 signaling differentially affects T-cell effector functions. Proc Natl Acad Sci USA. 2013; 110(27):E2480–9. doi: 10.1073/pnas.1305394110 23610399

30. Attinger A, Gavillet B, Chessex AV, Wiedemann N, Vuagniaux G. The inhibitor of apoptosis protein (IAP) antagonist Debio 1143 enhances the immune response to anti-PD1/L1 inhibitors in vitro and in vivo. Cancer Research. 2018; 78, 13 Supplement. doi: 10.1158/1538-7445.AM2018-4703

31. Dougan SK, Dougan M. Regulation of innate and adaptive antitumor immunity by IAP antagonists. Immunotherapy. 2018; 10(9):787–796. doi: 10.2217/imt-2017-0185 Epub 2018 May 29. 29807457

32. Beug ST, Cheung HH, LaCasse EC, Korneluk RG. Modulation of immune signalling by inhibitors of apoptosis. Trends Immunol. 2012;33(11):535–45. doi: 10.1016/j.it.2012.06.004 Epub 2012 Jul 24. Review. 22836014

33. Oberoi-Khanuja TK, Murali A, RajalingamK. IAPs on the move: role of inhibitors of apoptosis proteins in cell migration. Cell Death Dis. 2013; 4(9): e784. Published online 2013 Sep 5. doi: 10.1038/cddis.2013.311 24008728

34. Dai Y, Lawrence TS, Liang Xu L. Overcoming cancer therapy resistance by targeting inhibitors of apoptosis proteins and nuclear factor-kappa B. Am J Transl Res. 2009; 1(1): 1–15. 19966933

35. Verhagen AM, Coulson EJ, Vaux DL. Inhibitor of apoptosis proteins and their relatives: IAPs and other BIRPs. Genome Biol. 2001; 2(7): reviews3009.1–reviews3009.10.

36. Bobardt M, Kuo J, Chatterji U, Chanda S, Little SJ, Wiedemann N, et al. The inhibitor apoptosis protein antagonist Debio 1143 is an attractive HIV-1 latency reversal candidate. PLoS One. 2019; 14(2):e0211746. doi: 10.1371/journal.pone.0211746 30716099

37. Beug ST, Cheung HH, LaCasse EC, Korneluk RG. Modulation of immune signalling by inhibitors of apoptosis. Trends Immunol. 2012; 33(11):535–45. doi: 10.1016/j.it.2012.06.004 Epub 2012 Jul 24. Review. 22836014

38. Bai L, Smith DC, Wang S. Small-Molecule SMAC Mimetics as New Cancer Therapeutics. Pharmacol Ther. 2014; 144(1): 82–95. Published online 2014 May 16. doi: 10.1016/j.pharmthera.2014.05.007 24841289

39. Müller-Sienerth N, Dietz L, Holtz P, Kapp M, Grigoleit GU, Schmuck C, et al. SMAC mimetic BV6 induces cell death in monocytes and maturation of monocyte-derived dendritic cells. PLoS One 2011; 6(6):e21556. doi: 10.1371/journal.pone.0021556 Epub 2011 Jun 30. 21738708

40. Knights AJ, Fucikova J, Pasam A, Koernig S, Cebon J. Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy. Cancer Immunol Immunother. 2013; 62(2):321–35. doi: 10.1007/s00262-012-1342-1 Epub 2012 Aug 26. 22923192

41. Lecis D, De Cesare M, Perego P, Conti A, Corna E, Drago C, et al. Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity. Cell Death Dis. 2013;4:e920. doi: 10.1038/cddis.2013.449 24232096

42. Brinkmann K, Hombach A, Seeger JM, Wagner-Stippich D, Klubertz D, Krönke M, et al. Second mitochondria-derived activator of caspase (SMAC) mimetic potentiates tumor susceptibility toward natural killer cell-mediated killing. Leuk Lymphoma. 2014;55(3):645–51. doi: 10.3109/10428194.2013.807925 Epub 2013 Jun 26. 23697877

43. Nachmias B, Mizrahi S, Elmalech M, Lazar I, Ashhab Y, Gazit R, et al. Manipulation of NK cytotoxicity by the IAP family member Livin. Eur J Immunol. 2007;37(12):3467–76. doi: 10.1002/eji.200636600 18034418

44. Liu N, Tao Z, Blanc JM, Zaorsky NG, Sun Y, Vuagniaux G, et al. Debio 1143, an antagonist of multiple inhibitor-of-apoptosis proteins, activates apoptosis and enhances radiosensitization of non-small cell lung cancer cells in vitro. Am J Cancer Res. 2014; 4(6):943–51. eCollection 2014. 25520882

45. Matzinger O, Viertl D, Tsoutsou P, Kadi L, Rigotti S, Zanna C, et al. The radiosensitizing activity of the SMAC-mimetic, Debio 1143, is TNFα-mediated in head and neck squamous cell carcinoma. Radiother Oncol. 2015; 116(3):495–503. doi: 10.1016/j.radonc.2015.05.017 26096848

46. Langdon CG, Wiedemann N, Held MA, Mamillapalli R, Iyidogan P, Theodosakis N, et al. SMAC mimetic Debio 1143 synergizes with taxanes, topoisomerase inhibitors and bromodomain inhibitors to impede growth of lung adenocarcinoma cells. Oncotarget. 2015; 6(35):37410–25. doi: 10.18632/oncotarget.6138 26485762

47. Thibault B, Genre L, Le Naour A, Broca C, Mery E, Vuagniaux G, et al. DEBIO 1143, an IAP inhibitor, reverses carboplatin resistance in ovarian cancer cells and triggers apoptotic or necroptotic cell death. Sci Rep. 2018; 8(1):17862. doi: 10.1038/s41598-018-35860-z 30552344

48. Tao Z, McCall NS, Wiedemann N, Vuagniaux G, Yuan Z, Lu B. SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer. Clin Cancer Res. 2019; 25(3):1113–1124. doi: 10.1158/1078-0432.CCR-17-3852 30352911

49. Juergens RA, Chu QS, Renouf DJ, Laurie SA, Purcea D, McWhirter E, et al. A dose-finding study of the SMAC mimetic Debio 1143 when given in combination with avelumab to patients with advanced solid malignancies. Journal of Clinical Oncology. 2019; 37, no. 15_suppl (May 20 2019) 2599–2599. doi: 10.1200/JCO.2019.37.15_suppl.2599

50. Seung E, Dudek TE, Allen TM, Freeman GJ, Luster AD, Tager AM. PD-1 blockade in chronically HIV-1-infected humanized mice suppresses viral loads. PLoS One. 2013; 8(10):e77780. doi: 10.1371/journal.pone.0077780 24204962

51. Gallay PA, Chatterji U, Kirchhoff A, Gandarilla A, Gunawardana M, Pyles RB, et al. Prevention of Vaginal and Rectal HIV Transmission by Antiretroviral Combinations in Humanized Mice. PLoS One. 2017; 12(9):e0184303. doi: 10.1371/journal.pone.0184303 28880948

52. Gallay P, Chatterji U, Kirchhoff A, Gandarilla A, Baum M, Moss J. Protection Efficacy of C5A Against Vaginal and Rectal HIV Challenges in Humanized Mice. Open Virol J. 2018; 12:1–13. doi: 10.2174/1874357901812010001 eCollection 2018

53. Melkus MW, Estes JD, Padgett-Thomas A, Gatlin J, Denton PW, Othieno FA, et al. Humanized mice mount specific adaptive and innate immune response to EBV and TSST-1. Nat Med. 2006; 12: 1316–1322. doi: 10.1038/nm1431 17057712

54. Lan P, Tonomura N, Shimizu A, Wang S, Yang YG. Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation. Blood. 2006; 108:487–492. doi: 10.1182/blood-2005-11-4388 16410443

55. Sun Z, Denton PW, Estes JD, Othieno FA, Wei BL, Wege AK, et al. Intrarectal transmission, systemic infection and CD4. T cell depletion in humanized mice infected with HIV-1. J Exp Med. 2007; 204: 705–714. doi: 10.1084/jem.20062411 17389241

56. Palmer BE, Neff CP, Lecureux J, Ehler A, Dsouza M, Remling-Mulder L, et al. In vivo blockade of the PD-1 receptor suppresses HIV-1 viral loads and improves CD4+ T cell levels in humanized mice. J Immunol. 2013; 190(1):211–9. doi: 10.4049/jimmunol.1201108 23209326

57. Brainard DM, Seung E, Frahm N, Cariappa A, Bailey CC, Hart WK, et al. Induction of robust cellular and humoral virus-specific adaptive immune responses in human immunodeficiency virus-infected humanized BLT mice. J Virol. 2009; 83(14):7305–21. doi: 10.1128/JVI.02207-08 Epub 2009 May 6. 19420076

58. Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med. 2006; 12(10):1198–202. Epub 2006 Aug 20. Erratum in: Nat Med. 2006 Nov;12(11):1329. doi: 10.1038/nm1482 16917489

59. Dougan M, Dougan S, Slisz J, Firestone B, Vanneman M, Draganov D, et al. IAP inhibitors enhance co-stimulation to promote tumor immunity. J Exp Med. 2010; 207(10):2195–206. doi: 10.1084/jem.20101123 Epub 2010 Sep 13. 20837698

60. Denton PW, Olesen R, Choudhary SK, Archin NM, Wahl A, Swanson MD, et al. Generation of HIV latency in humanized BLT mice. J Virol. 2012; 86(1):630–4. doi: 10.1128/JVI.06120-11 22013053

61. Marsden MD, Kovochich M, Suree N, Shimizu S, Mehta R, Cortado R, et al. HIV latency in the humanized BLT mouse. J Virol. 2012; 86(1):339–47. doi: 10.1128/JVI.06366-11 22072769


Článek vyšel v časopise

PLOS One


2020 Číslo 1