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Cancer Immunology, Immunotherapy

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01.02.2013 | Original article

Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy

verfasst von: Ashley J. Knights, Jitka Fucikova, Anupama Pasam, Sandra Koernig, Jonathan Cebon

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 2/2013

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Abstract

Inhibitor of apoptosis proteins (IAPs) are critical in regulating apoptosis resistance in cancer. Antagonists of IAPs, such as LCL161, are in clinical development and show promise as anti-cancer agents for solid and hematological cancers, with preliminary data suggesting they may act as immunomodulators. IAP antagonists hypersensitize tumor cells to TNF-α-mediated apoptosis, an effect that may work in synergy with that of cancer vaccines. This study aimed to further investigate the immunomodulatory properties of LCL161 on human immune subsets. T lymphocytes treated with LCL161 demonstrated significantly enhanced cytokine secretion upon activation, with little effect on CD4 and CD8 T-cell survival or proliferation. LCL161 treatment of peripheral blood mononuclear cells significantly enhanced priming of naïve T cells with synthetic peptides in vitro. Myeloid dendritic cells underwent phenotypic maturation upon IAP antagonism and demonstrated a reduced capacity to cross-present a tumor antigen-based vaccine. These effects are potentially mediated through an observed activation of the canonical and non-canonical NF-κB pathways, following IAP antagonism with a resulting upregulation of anti-apoptotic molecules. In conclusion, this study demonstrated the immunomodulatory properties of antagonists at physiologically relevant concentrations and indicates their combination with immunotherapy requires further investigation.

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Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723. doi:10.1056/NEJMoa1003466 PubMedCrossRef

Kantoff PW, Higano CS, Shore ND et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411–422. doi:10.1056/NEJMoa1001294 PubMedCrossRef

Heine A, Held SA, Bringmann A, Holderried TA, Brossart P (2011) Immunomodulatory effects of anti-angiogenic drugs. Leukemia 25:899–905. doi:10.1038/leu.2011.24 PubMedCrossRef

Ott PA, Adams S (2011) Small-molecule protein kinase inhibitors and their effects on the immune system: implications for cancer treatment. Immunotherapy 3:213–227. doi:10.2217/imt.10.99 PubMedCrossRef

Du C, Fang M, Li Y, Li L, Wang X (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102:33–42PubMedCrossRef

Yang QH, Du C (2004) Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells. J Biol Chem 279:16963–16970. doi:10.1074/jbc.M401253200 PubMedCrossRef

Varfolomeev E, Vucic D (2011) Inhibitor of apoptosis proteins: fascinating biology leads to attractive tumor therapeutic targets. Future Oncol 7:633–648. doi:10.2217/fon.11.40 PubMedCrossRef

Vucic D, Fairbrother WJ (2007) The inhibitor of apoptosis proteins as therapeutic targets in cancer. Clin Cancer Res 13:5995–6000. doi:10.1158/1078-0432.CCR-07-0729 PubMedCrossRef

Varfolomeev E, Blankenship JW, Wayson SM et al (2007) IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFalpha-dependent apoptosis. Cell 131:669–681. doi:10.1016/j.cell.2007.10.030 PubMedCrossRef

10.

Vince JE, Wong WW, Khan N et al (2007) IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell 131:682–693. doi:10.1016/j.cell.2007.10.037 PubMedCrossRef

11.

Wu H, Tschopp J, Lin SC (2007) Smac mimetics and TNFalpha: a dangerous liaison? Cell 131:655–658. doi:10.1016/j.cell.2007.10.042 PubMedCrossRef

12.

Dai Y, Liu M, Tang W, Li Y, Lian J, Lawrence TS, Xu L (2009) A Smac-mimetic sensitizes prostate cancer cells to TRAIL-induced apoptosis via modulating both IAPs and NF-κB. BMC Cancer 9:392. doi:10.1186/1471-2407-9-392 PubMedCrossRef

13.

Varfolomeev E, Alicke B, Elliott JM et al (2009) X chromosome-linked inhibitor of apoptosis regulates cell death induction by proapoptotic receptor agonists. J Biol Chem 284:34553–34560. doi:10.1074/jbc.M109.040139 PubMedCrossRef

14.

Fakler M, Loeder S, Vogler M, Schneider K, Jeremias I, Debatin KM, Fulda S (2009) Small molecule XIAP inhibitors cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells and overcome Bcl-2-mediated resistance. Blood 113:1710–1722. doi:10.1182/blood-2007-09-114314 PubMedCrossRef

15.

Loeder S, Zenz T, Schnaiter A, Mertens D, Winkler D, Dohner H, Debatin KM, Stilgenbauer S, Fulda S (2009) A novel paradigm to trigger apoptosis in chronic lymphocytic leukemia. Cancer Res 69:8977–8986. doi:10.1158/0008-5472.CAN-09-2604 PubMedCrossRef

16.

Matsuzawa A, Tseng PH, Vallabhapurapu S, Luo JL, Zhang W, Wang H, Vignali DA, Gallagher E, Karin M (2008) Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex. Science 321:663–668. doi:10.1126/science.1157340 PubMedCrossRef

17.

Vallabhapurapu S, Matsuzawa A, Zhang W, Tseng PH, Keats JJ, Wang H, Vignali DA, Bergsagel PL, Karin M (2008) Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-κB signaling. Nat Immunol 9:1364–1370. doi:10.1038/ni.1678 PubMedCrossRef

18.

Gardam S, Turner VM, Anderton H, Limaye S, Basten A, Koentgen F, Vaux DL, Silke J, Brink R (2011) Deletion of cIAP1 and cIAP2 in murine B lymphocytes constitutively activates cell survival pathways and inactivates the germinal center response. Blood 117:4041–4051. doi:10.1182/blood-2010-10-312793 PubMedCrossRef

19.

Tseng PH, Matsuzawa A, Zhang W, Mino T, Vignali DA, Karin M (2010) Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat Immunol 11:70–75. doi:10.1038/ni.1819 PubMedCrossRef

20.

Dupoux A, Cartier J, Cathelin S, Filomenko R, Solary E, Dubrez-Daloz L (2009) cIAP1-dependent TRAF2 degradation regulates the differentiation of monocytes into macrophages and their response to CD40 ligand. Blood 113:175–185. doi:10.1182/blood-2008-02-137919 PubMedCrossRef

21.

Conte D, Holcik M, Lefebvre CA, Lacasse E, Picketts DJ, Wright KE, Korneluk RG (2006) Inhibitor of apoptosis protein cIAP2 is essential for lipopolysaccharide-induced macrophage survival. Mol Cell Biol 26:699–708. doi:10.1128/MCB.26.2.699-708.2006 PubMedCrossRef

22.

Waldele K, Silbermann K, Schneider G, Ruckes T, Cullen BR, Grassmann R (2006) Requirement of the human T-cell leukemia virus (HTLV-1) tax-stimulated HIAP-1 gene for the survival of transformed lymphocytes. Blood 107:4491–4499. doi:10.1182/blood-2005-08-3138 PubMedCrossRef

23.

Zane L, Sibon D, Legras C et al (2010) Clonal expansion of HTLV-1 positive CD8+ cells relies on cIAP-2 but not on c-FLIP expression. Virology 407:341–351. doi:10.1016/j.virol.2010.07.023 PubMedCrossRef

24.

Dougan M, Dougan S, Slisz J et al (2010) IAP inhibitors enhance co-stimulation to promote tumor immunity. J Exp Med 207:2195–2206. doi:10.1084/jem.20101123 PubMedCrossRef

25.

Infante JR, Dees EC, Burris HAI et al (2010) A phase I study of LCL161, an oral IAP inhibitor, in patients with advanced cancer. The 101st annual meeting of the American Association for Cancer Research, Washington

26.

Houghton PJ, Kang MH, Reynolds CP et al (2011) Initial testing (Stage 1) of LCL161, a SMAC mimetic, by the pediatric preclinical testing program. Pediatr Blood Cancer. doi:10.1002/pbc.23167

27.

Weisberg E, Ray A, Barrett R et al (2010) Smac mimetics: implications for enhancement of targeted therapies in leukemia. Leukemia 24:2100–2109. doi:10.1038/leu.2010.212 PubMedCrossRef

28.

Knights AJ, Nuber N, Thomson CW et al (2009) Modified tumour antigen-encoding mRNA facilitates the analysis of naturally occurring and vaccine-induced CD4 and CD8 T cells in cancer patients. Cancer Immunol Immunother 58:325–338. doi:10.1007/s00262-008-0556-8 PubMedCrossRef

29.

Robson NC, McAlpine T, Knights AJ, Schnurr M, Shin A, Chen W, Maraskovsky E, Cebon J (2010) Processing and cross-presentation of individual HLA-A, -B, or -C epitopes from NY-ESO-1 or an HLA-A epitope for Melan-A differ according to the mode of antigen delivery. Blood 116:218–225. doi:10.1182/blood-2009-10-249458 PubMedCrossRef

30.

Platt CD, Ma JK, Chalouni C, Ebersold M, Bou-Reslan H, Carano RA, Mellman I, Delamarre L (2010) Mature dendritic cells use endocytic receptors to capture and present antigens. Proc Natl Acad Sci USA 107:4287–4292. doi:10.1073/pnas.0910609107 PubMedCrossRef

31.

Chauhan D, Neri P, Velankar M et al (2007) Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM). Blood 109:1220–1227. doi:10.1182/blood-2006-04-015149 PubMedCrossRef

32.

Zippelius A, Pittet MJ, Batard P et al (2002) Thymic selection generates a large T cell pool recognizing a self-peptide in humans. J Exp Med 195:485–494PubMedCrossRef

33.

Duewell P, Kisser U, Heckelsmiller K et al (2011) ISCOMATRIX adjuvant combines immune activation with antigen delivery to dendritic cells in vivo leading to effective cross-priming of CD8+ T Cells. J Immunol 187:55–63. doi:10.4049/jimmunol.1004114 PubMedCrossRef

34.

Klein O, Schmidt C, Knights A, Davis ID, Chen W, Cebon J (2011) Melanoma vaccines: developments over the past 10 years. Expert Rev Vaccin 10:853–873. doi:10.1586/erv.11.74 CrossRef

35.

Ouaaz F, Arron J, Zheng Y, Choi Y, Beg AA (2002) Dendritic cell development and survival require distinct NF-κB subunits. Immunity 16:257–270PubMedCrossRef

36.

Hayden MS, Ghosh S (2004) Signaling to NF-κB. Genes Dev 18:2195–2224. doi:10.1101/gad.1228704 PubMedCrossRef

37.

Bonizzi G, Karin M (2004) The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25:280–288. doi:10.1016/j.it.2004.03.008 PubMedCrossRef

38.

Davis ID, Chen W, Jackson H et al (2004) Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad integrated antibody and CD4(+) and CD8(+) T cell responses in humans. Proc Natl Acad Sci USA 101:10697–10702. doi:10.1073/pnas.0403572101 PubMedCrossRef

39.

Nicholaou T, Ebert L, Davis ID, Robson N, Klein O, Maraskovsky E, Chen W, Cebon J (2006) Directions in the immune targeting of cancer: lessons learned from the cancer-testis Ag NY-ESO-1. Immunol Cell Biol 84:303–317. doi:10.1111/j.1440-1711.2006.01446.x PubMedCrossRef

40.

Garrett WS, Chen LM, Kroschewski R, Ebersold M, Turley S, Trombetta S, Galan JE, Mellman I (2000) Developmental control of endocytosis in dendritic cells by Cdc42. Cell 102:325–334PubMedCrossRef

41.

Hickman-Miller HD, Yewdell JW (2006) Youth has its privileges: maturation inhibits DC cross-priming. Nat Immunol 7:125–126. doi:10.1038/ni0206-125 PubMedCrossRef

42.

Schnurr M, Orban M, Robson NC, Shin A, Braley H, Airey D, Cebon J, Maraskovsky E, Endres S (2009) ISCOMATRIX adjuvant induces efficient cross-presentation of tumor antigen by dendritic cells via rapid cytosolic antigen delivery and processing via tripeptidyl peptidase II. J Immunol 182:1253–1259PubMedCrossRef

43.

van de Laar L, van den Bosch A, van der Kooij SW, Janssen HL, Coffer PJ, van Kooten C, Woltman AM (2010) A nonredundant role for canonical NF-κB in human myeloid dendritic cell development and function. J Immunol 185:7252–7261. doi:10.4049/jimmunol.1000672 PubMedCrossRef

44.

O’Sullivan BJ, Thomas R (2002) CD40 ligation conditions dendritic cell antigen-presenting function through sustained activation of NF-κB. J Immunol 168:5491–5498PubMed

45.

Li M, Zhang X, Zheng X et al (2007) Immune modulation and tolerance induction by RelB-silenced dendritic cells through RNA interference. J Immunol 178:5480–5487PubMed

46.

Carreno LJ, Riedel CA, Kalergis AM (2011) Induction of tolerogenic dendritic cells by NF-κB blockade and Fcgamma receptor modulation. Methods Mol Biol 677:339–353. doi:10.1007/978-1-60761-869-0_22 PubMedCrossRef

47.

Hernandez A, Burger M, Blomberg BB et al (2007) Inhibition of NF-κB during human dendritic cell differentiation generates anergy and regulatory T-cell activity for one but not two human leukocyte antigen DR mismatches. Hum Immunol 68:715–729. doi:10.1016/j.humimm.2007.05.010 PubMedCrossRef

48.

Gasparini C, Foxwell BM, Feldmann M (2009) RelB/p50 regulates CCL19 production, but fails to promote human DC maturation. Eur J Immunol 39:2215–2223. doi:10.1002/eji.200939209 PubMedCrossRef

49.

Schnurr M, Chen Q, Shin A et al (2005) Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery. Blood 105:2465–2472. doi:10.1182/blood-2004-08-3105 PubMedCrossRef

Titel: Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy
verfasst von: Ashley J. Knights
Jitka Fucikova
Anupama Pasam
Sandra Koernig
Jonathan Cebon
Publikationsdatum: 01.02.2013
Verlag: Springer-Verlag
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 2/2013
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-012-1342-1

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Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy

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