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Erschienen in: Cancer Immunology, Immunotherapy 7/2013

01.07.2013 | Original Article

Blocking retinoic acid receptor-α enhances the efficacy of a dendritic cell vaccine against tumours by suppressing the induction of regulatory T cells

verfasst von: Karen C. Galvin, Lydia Dyck, Neil A. Marshall, Anna M. Stefanska, Kevin P. Walsh, Barry Moran, Sarah C. Higgins, Lara S. Dungan, Kingston H. G. Mills

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 7/2013

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Abstract

The immune system has evolved regulatory mechanisms to control immune responses to self-antigens. Regulatory T (Treg) cells play a pivotal role in maintaining immune tolerance, but tumour growth is associated with local immunosuppression, which can subvert effector immune responses. Indeed, the induction and recruitment of Treg cells by tumours is a major barrier in the development of effective immunotherapeutics and vaccines against cancer. Retinoic acid (RA) has been shown to promote conversion of naïve T cells into Treg cells. This study addresses the hypothesis that blocking RA receptor alpha (RARα) may enhance the efficacy of a tumour vaccine by inhibiting the induction of Treg cells. We found that RA significantly enhanced TGF-β-induced expression of Foxp3 on naïve and committed T cells in vitro and that this was blocked by an antagonist of RARα (RARi). In addition, RARi significantly suppressed TGF-β and IL-10 and enhanced IL-12 production by dendritic cells (DC) in response to killed tumour cells or TLR agonists. Furthermore, RARi augmented the efficacy of an antigen-pulsed and TLR-activated DC vaccine, significantly attenuating growth of B16 tumours in vivo and enhancing survival of mice. This protective effect was associated with significant reduction in tumour-infiltrating FoxP3+ and IL-10+ Treg cells and a corresponding increase in tumour-infiltrating CD4+ and CD8+ T cells that secreted IFN-γ. Our findings demonstrate that RARα is an important target for the development of effective anti-tumour immunotherapeutics and for improving the efficacy of cancer vaccines.
Literatur
1.
Zurück zum Zitat Smith SM, Levy NS, Hayes CE (1987) Impaired immunity in vitamin A-deficient mice. J Nutr 117:857–865PubMed Smith SM, Levy NS, Hayes CE (1987) Impaired immunity in vitamin A-deficient mice. J Nutr 117:857–865PubMed
2.
Zurück zum Zitat Molenaar R, Knippenberg M, Goverse G, Olivier BJ, de Vos AF, O’Toole T, Mebius RE (2011) Expression of retinaldehyde dehydrogenase enzymes in mucosal dendritic cells and gut-draining lymph node stromal cells is controlled by dietary vitamin A. J Immunol 186:1934–1942. doi:10.4049/jimmunol.1001672 PubMedCrossRef Molenaar R, Knippenberg M, Goverse G, Olivier BJ, de Vos AF, O’Toole T, Mebius RE (2011) Expression of retinaldehyde dehydrogenase enzymes in mucosal dendritic cells and gut-draining lymph node stromal cells is controlled by dietary vitamin A. J Immunol 186:1934–1942. doi:10.​4049/​jimmunol.​1001672 PubMedCrossRef
3.
Zurück zum Zitat Mic FA, Molotkov A, Fan X, Cuenca AE, Duester G (2000) RALDH3, a retinaldehyde dehydrogenase that generates retinoic acid, is expressed in the ventral retina, otic vesicle and olfactory pit during mouse development. Mech Dev 97:227–230PubMedCrossRef Mic FA, Molotkov A, Fan X, Cuenca AE, Duester G (2000) RALDH3, a retinaldehyde dehydrogenase that generates retinoic acid, is expressed in the ventral retina, otic vesicle and olfactory pit during mouse development. Mech Dev 97:227–230PubMedCrossRef
4.
Zurück zum Zitat Schambach F, Schupp M, Lazar MA, Reiner SL (2007) Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur J Immunol 37:2396–2399. doi:10.1002/eji.200737621 PubMedCrossRef Schambach F, Schupp M, Lazar MA, Reiner SL (2007) Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur J Immunol 37:2396–2399. doi:10.​1002/​eji.​200737621 PubMedCrossRef
5.
Zurück zum Zitat Lefebvre B, Brand C, Lefebvre P, Ozato K (2002) Chromosomal integration of retinoic acid response elements prevents cooperative transcriptional activation by retinoic acid receptor and retinoid X receptor. Mol Cell Biol 22:1446–1459PubMedCrossRef Lefebvre B, Brand C, Lefebvre P, Ozato K (2002) Chromosomal integration of retinoic acid response elements prevents cooperative transcriptional activation by retinoic acid receptor and retinoid X receptor. Mol Cell Biol 22:1446–1459PubMedCrossRef
7.
Zurück zum Zitat Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F (2007) A functionally specialized population of mucosal CD103 + DCs induces Foxp3 + regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 204:1757–1764. doi:10.1084/jem.20070590 PubMedCrossRef Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F (2007) A functionally specialized population of mucosal CD103 + DCs induces Foxp3 + regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 204:1757–1764. doi:10.​1084/​jem.​20070590 PubMedCrossRef
8.
Zurück zum Zitat Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B (2007) Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol 8:1086–1094. doi:10.1038/ni1511 PubMedCrossRef Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B (2007) Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol 8:1086–1094. doi:10.​1038/​ni1511 PubMedCrossRef
9.
Zurück zum Zitat Elias KM, Laurence A, Davidson TS, Stephens G, Kanno Y, Shevach EM, O’Shea JJ (2008) Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 111:1013–1020. doi:10.1182/blood-2007-06-096438 PubMedCrossRef Elias KM, Laurence A, Davidson TS, Stephens G, Kanno Y, Shevach EM, O’Shea JJ (2008) Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 111:1013–1020. doi:10.​1182/​blood-2007-06-096438 PubMedCrossRef
10.
Zurück zum Zitat Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y (2007) Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 204:1775–1785. doi:10.1084/jem.20070602 PubMedCrossRef Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y (2007) Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 204:1775–1785. doi:10.​1084/​jem.​20070602 PubMedCrossRef
13.
Zurück zum Zitat Cha HR, Chang SY, Chang JH, Kim JO, Yang JY, Kim CH, Kweon MN (2010) Downregulation of Th17 cells in the small intestine by disruption of gut flora in the absence of retinoic acid. J Immunol. 184:6799–6806. doi:10.4049/jimmunol.0902944 PubMedCrossRef Cha HR, Chang SY, Chang JH, Kim JO, Yang JY, Kim CH, Kweon MN (2010) Downregulation of Th17 cells in the small intestine by disruption of gut flora in the absence of retinoic acid. J Immunol. 184:6799–6806. doi:10.​4049/​jimmunol.​0902944 PubMedCrossRef
14.
Zurück zum Zitat Jarnicki AG, Lysaght J, Todryk S, Mills KHG (2006) Suppression of antitumor immunity by IL-10 and TGF-beta-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cell. J Immunol 177:896–904PubMed Jarnicki AG, Lysaght J, Todryk S, Mills KHG (2006) Suppression of antitumor immunity by IL-10 and TGF-beta-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cell. J Immunol 177:896–904PubMed
16.
Zurück zum Zitat Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59:3128–3133PubMed Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59:3128–3133PubMed
17.
Zurück zum Zitat Coe D, Addey C, White M, Simpson E, Dyson J, Chai JG (2010) The roles of antigen-specificity, responsiveness to transforming growth factor-beta and antigen-presenting cell subsets in tumour-induced expansion of regulatory T cells. Immunology 131:556–569. doi:10.1111/j.1365-2567.2010.03328.x PubMedCrossRef Coe D, Addey C, White M, Simpson E, Dyson J, Chai JG (2010) The roles of antigen-specificity, responsiveness to transforming growth factor-beta and antigen-presenting cell subsets in tumour-induced expansion of regulatory T cells. Immunology 131:556–569. doi:10.​1111/​j.​1365-2567.​2010.​03328.​x PubMedCrossRef
18.
19.
Zurück zum Zitat Small EJ, Tchekmedyian NS, Rini BI, Fong L, Lowy I, Allison JP (2007) A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res Off J Am Assoc Cancer Res 13:1810–1815. doi:10.1158/1078-0432.CCR-06-2318 CrossRef Small EJ, Tchekmedyian NS, Rini BI, Fong L, Lowy I, Allison JP (2007) A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res Off J Am Assoc Cancer Res 13:1810–1815. doi:10.​1158/​1078-0432.​CCR-06-2318 CrossRef
20.
Zurück zum Zitat Marshall NA, Galvin KC, Corcoran AM, Boon L, Higgs R, Mills KH (2012) Immunotherapy with PI3K inhibitor and Toll-like receptor agonist induces IFN-gamma+ IL-17+ polyfunctional T cells that mediate rejection of murine tumors. Cancer Res 72:581–591. doi:10.1158/0008-5472.CAN-11-0307 PubMedCrossRef Marshall NA, Galvin KC, Corcoran AM, Boon L, Higgs R, Mills KH (2012) Immunotherapy with PI3K inhibitor and Toll-like receptor agonist induces IFN-gamma+ IL-17+ polyfunctional T cells that mediate rejection of murine tumors. Cancer Res 72:581–591. doi:10.​1158/​0008-5472.​CAN-11-0307 PubMedCrossRef
21.
Zurück zum Zitat Conroy H, Galvin KC, Higgins SC, Mills KH (2012) Gene silencing of TGF-beta1 enhances antitumor immunity induced with a dendritic cell vaccine by reducing tumor-associated regulatory T cells. Cancer Immunol Immunother CII 61:425–431. doi:10.1007/s00262-011-1188-y CrossRef Conroy H, Galvin KC, Higgins SC, Mills KH (2012) Gene silencing of TGF-beta1 enhances antitumor immunity induced with a dendritic cell vaccine by reducing tumor-associated regulatory T cells. Cancer Immunol Immunother CII 61:425–431. doi:10.​1007/​s00262-011-1188-y CrossRef
22.
Zurück zum Zitat Napoli JL (1999) Retinoic acid: its biosynthesis and metabolism. Prog Nucleic Acid Res Mol Biol 63:139–188PubMedCrossRef Napoli JL (1999) Retinoic acid: its biosynthesis and metabolism. Prog Nucleic Acid Res Mol Biol 63:139–188PubMedCrossRef
24.
Zurück zum Zitat Dhodapkar MV, Steinman RM, Krasovsky J, Munz C, Bhardwaj N (2001) Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 193:233–238PubMedCrossRef Dhodapkar MV, Steinman RM, Krasovsky J, Munz C, Bhardwaj N (2001) Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 193:233–238PubMedCrossRef
25.
Zurück zum Zitat Schuler-Thurner B, Schultz ES, Berger TG et al (2002) Rapid induction of tumor-specific type 1 T helper cells in metastatic melanoma patients by vaccination with mature, cryopreserved, peptide-loaded monocyte-derived dendritic cells. J Exp Med 195:1279–1288PubMedCrossRef Schuler-Thurner B, Schultz ES, Berger TG et al (2002) Rapid induction of tumor-specific type 1 T helper cells in metastatic melanoma patients by vaccination with mature, cryopreserved, peptide-loaded monocyte-derived dendritic cells. J Exp Med 195:1279–1288PubMedCrossRef
27.
Zurück zum Zitat Lacarrubba F, Potenza MC, Gurgone S, Micali G (2011) Successful treatment and management of large superficial basal cell carcinomas with topical imiquimod 5% cream: a case series and review. J Dermatolog Treat 22:353–358. doi:10.3109/09546634.2010.548503 PubMedCrossRef Lacarrubba F, Potenza MC, Gurgone S, Micali G (2011) Successful treatment and management of large superficial basal cell carcinomas with topical imiquimod 5% cream: a case series and review. J Dermatolog Treat 22:353–358. doi:10.​3109/​09546634.​2010.​548503 PubMedCrossRef
29.
Zurück zum Zitat Jarnicki AG, Conroy H, Brereton C et al (2008) Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics. J Immunol 180:3797–3806PubMed Jarnicki AG, Conroy H, Brereton C et al (2008) Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics. J Immunol 180:3797–3806PubMed
30.
Zurück zum Zitat Oble DA, Loewe R, Yu P, Mihm MC Jr (2009) Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma. Cancer Immun 9:3PubMed Oble DA, Loewe R, Yu P, Mihm MC Jr (2009) Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma. Cancer Immun 9:3PubMed
31.
Zurück zum Zitat Berard F, Blanco P, Davoust J et al (2000) Cross-priming of naive CD8 T cells against melanoma antigens using dendritic cells loaded with killed allogeneic melanoma cells. J Exp Med 192:1535–1544PubMedCrossRef Berard F, Blanco P, Davoust J et al (2000) Cross-priming of naive CD8 T cells against melanoma antigens using dendritic cells loaded with killed allogeneic melanoma cells. J Exp Med 192:1535–1544PubMedCrossRef
Metadaten
Titel
Blocking retinoic acid receptor-α enhances the efficacy of a dendritic cell vaccine against tumours by suppressing the induction of regulatory T cells
verfasst von
Karen C. Galvin
Lydia Dyck
Neil A. Marshall
Anna M. Stefanska
Kevin P. Walsh
Barry Moran
Sarah C. Higgins
Lara S. Dungan
Kingston H. G. Mills
Publikationsdatum
01.07.2013
Verlag
Springer-Verlag
Erschienen in
Cancer Immunology, Immunotherapy / Ausgabe 7/2013
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-013-1432-8

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