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Erschienen in: Cancer Immunology, Immunotherapy 12/2011

01.12.2011 | Original article

Signals through 4-1BB inhibit T regulatory cells by blocking IL-9 production enhancing antitumor responses

verfasst von: Shannon E. Smith, Dominique B. Hoelzinger, Ana Lucia Dominguez, Jacques Van Snick, Joseph Lustgarten

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 12/2011

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Abstract

Previous studies from our laboratory indicate that intratumoral (i.t.) injections of CpG-ODN are the most effective adjuvant strategy to induce an antitumor immune response in tolerant BALB-neuT mice but insufficient for tumor eradication. We evaluated whether this treatment strategy could be enhanced by the presence of anti-OX40 and anti-4-1BB antibodies. Treatment with anti-4-1BB resulted in a greater antitumor response than anti-OX40. The results indicate that anti-4-1BB but not anti-OX40 inhibited the suppressive function of T regulatory cells (Tregs). Through microarray analysis we evaluated the mechanism by which anti-4-1BB inhibits iTregs using the Foxp3-GFP mice. We observed specific transcriptional differences in over 100 genes in iTregs treated with anti-4-1BB, and selected those genes that remained unaffected by exposure to anti-OX40. Interleukin 9 was transcriptionally down-regulated 28-fold by anti-4-1BB treatment, and this was matched by a significant reduction of IL-9 secretion by iTregs. Furthermore, blockade of the common γ-chain receptor resulted in the inhibition of iTreg-suppressive function. More importantly, neutralization of IL-9 plus i.t. injections of CpG-ODN induces tumor rejection in BALB-neuT and MUC-1 tolerant transgenic mice. These results indicate that IL-9 plays a role in iTreg biology during the tumor inflammatory process enhancing/promoting the suppressive function of these cells and that the blockade of IL-9 could serve as a novel strategy to modulate the function of Tregs to enhance the antitumor effect of tumor vaccines.
Literatur
1.
Zurück zum Zitat Gross S, Walden P (2008) Immunosuppressive mechanisms in human tumors: why we still cannot cure cancer. Immunol Lett 116:7–14PubMedCrossRef Gross S, Walden P (2008) Immunosuppressive mechanisms in human tumors: why we still cannot cure cancer. Immunol Lett 116:7–14PubMedCrossRef
2.
Zurück zum Zitat Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787PubMedCrossRef Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787PubMedCrossRef
3.
Zurück zum Zitat Leffers N, Gooden MJ, de Jong RA, Hoogeboom BN, ten Hoor KA, Hollema H, Boezen HM, van der Zee AG, Daemen T, Nijman HW (2009) Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 58:449–459PubMedCrossRef Leffers N, Gooden MJ, de Jong RA, Hoogeboom BN, ten Hoor KA, Hollema H, Boezen HM, van der Zee AG, Daemen T, Nijman HW (2009) Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 58:449–459PubMedCrossRef
4.
Zurück zum Zitat Horwitz DA, Zheng SG, Gray JD (2008) Natural and TGF-beta-induced Foxp3(+)CD4(+) CD25(+) regulatory T cells are not mirror images of each other. Trends Immunol 29:429–435PubMedCrossRef Horwitz DA, Zheng SG, Gray JD (2008) Natural and TGF-beta-induced Foxp3(+)CD4(+) CD25(+) regulatory T cells are not mirror images of each other. Trends Immunol 29:429–435PubMedCrossRef
5.
Zurück zum Zitat Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM (2003) Conversion of peripheral CD4 + CD25− naive T cells to CD4 + CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198:1875–1886PubMedCrossRef Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM (2003) Conversion of peripheral CD4 + CD25− naive T cells to CD4 + CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198:1875–1886PubMedCrossRef
6.
Zurück zum Zitat Zhou G, Levitsky HI (2007) Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance. J Immunol 178:2155–2162PubMed Zhou G, Levitsky HI (2007) Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance. J Immunol 178:2155–2162PubMed
7.
Zurück zum Zitat Wada J, Suzuki H, Fuchino R, Yamasaki A, Nagai S, Yanai K, Koga K, Nakamura M, Tanaka M, Morisaki T, Katano M (2009) The contribution of vascular endothelial growth factor to the induction of regulatory T-cells in malignant effusions. Anticancer Res 29:881–888PubMed Wada J, Suzuki H, Fuchino R, Yamasaki A, Nagai S, Yanai K, Koga K, Nakamura M, Tanaka M, Morisaki T, Katano M (2009) The contribution of vascular endothelial growth factor to the induction of regulatory T-cells in malignant effusions. Anticancer Res 29:881–888PubMed
8.
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
9.
Zurück zum Zitat Kretschmer K, Apostolou I, Verginis P, von Boehmer H (2008) Regulatory T cells and antigen-specific tolerance. Chem Immunol Allergy 94:8–15PubMedCrossRef Kretschmer K, Apostolou I, Verginis P, von Boehmer H (2008) Regulatory T cells and antigen-specific tolerance. Chem Immunol Allergy 94:8–15PubMedCrossRef
10.
Zurück zum Zitat Dominguez AL, Lustgarten J (2008) Implications of aging and self-tolerance on the generation of immune and antitumor immune responses. Cancer Res 68:5423–5431PubMedCrossRef Dominguez AL, Lustgarten J (2008) Implications of aging and self-tolerance on the generation of immune and antitumor immune responses. Cancer Res 68:5423–5431PubMedCrossRef
11.
Zurück zum Zitat Hoelzinger DB, Smith SE, Mirza N, Dominguez AL, Manrique SZ, Lustgarten J (2010) Blockade of CCL1 inhibits T regulatory cell suppressive function enhancing tumor immunity without affecting T effector responses. J Immunol 184:6833–6842PubMedCrossRef Hoelzinger DB, Smith SE, Mirza N, Dominguez AL, Manrique SZ, Lustgarten J (2010) Blockade of CCL1 inhibits T regulatory cell suppressive function enhancing tumor immunity without affecting T effector responses. J Immunol 184:6833–6842PubMedCrossRef
12.
Zurück zum Zitat Couper KN, Lanthier PA, Perona-Wright G, Kummer LW, Chen W, Smiley ST, Mohrs M, Johnson LL (2009) Anti-CD25 antibody-mediated depletion of effector T cell populations enhances susceptibility of mice to acute but not chronic Toxoplasma gondii infection. J Immunol 182:3985–3994PubMedCrossRef Couper KN, Lanthier PA, Perona-Wright G, Kummer LW, Chen W, Smiley ST, Mohrs M, Johnson LL (2009) Anti-CD25 antibody-mediated depletion of effector T cell populations enhances susceptibility of mice to acute but not chronic Toxoplasma gondii infection. J Immunol 182:3985–3994PubMedCrossRef
13.
Zurück zum Zitat Barton G, Medzhitov R (2002) Control of adaptive immune responses by Toll-like receptors. Curr Opin Immunol 14:380–383PubMedCrossRef Barton G, Medzhitov R (2002) Control of adaptive immune responses by Toll-like receptors. Curr Opin Immunol 14:380–383PubMedCrossRef
14.
Zurück zum Zitat Kaisho T, Akira S (2002) Toll-like receptors as adjuvant receptors. Biochim Biophy Acta 1589:1–13CrossRef Kaisho T, Akira S (2002) Toll-like receptors as adjuvant receptors. Biochim Biophy Acta 1589:1–13CrossRef
15.
Zurück zum Zitat Huang Q, Liu D, Majewski P, Schulte L, Korn J, Young R, Lander E, Hacohen N (2001) The plasticity of dendritic cell responses to pathogens and their components. Science 294:870–875PubMedCrossRef Huang Q, Liu D, Majewski P, Schulte L, Korn J, Young R, Lander E, Hacohen N (2001) The plasticity of dendritic cell responses to pathogens and their components. Science 294:870–875PubMedCrossRef
16.
17.
Zurück zum Zitat Sharma S, Dominguez AL, Manrique SZ, Cavallo F, Sakaguchi S, Lustgarten J (2008) Systemic targeting of CpG-ODN to the tumor microenvironment with anti-neu-CpG hybrid molecule and T regulatory cell depletion induces memory responses in BALB-neuT tolerant mice. Cancer Res 68:7530–7540PubMedCrossRef Sharma S, Dominguez AL, Manrique SZ, Cavallo F, Sakaguchi S, Lustgarten J (2008) Systemic targeting of CpG-ODN to the tumor microenvironment with anti-neu-CpG hybrid molecule and T regulatory cell depletion induces memory responses in BALB-neuT tolerant mice. Cancer Res 68:7530–7540PubMedCrossRef
18.
Zurück zum Zitat Watts TH (2005) TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 23:23–68PubMedCrossRef Watts TH (2005) TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 23:23–68PubMedCrossRef
19.
Zurück zum Zitat Cuadros C, Dominguez AL, Frost GI, Borgstrom P, Lustgarten J (2003) Cooperative effect between immunotherapy and antiangiogenic therapy leads to effective tumor rejection in tolerant Her-2/neu mice. Cancer Res 63:5895–5901PubMed Cuadros C, Dominguez AL, Frost GI, Borgstrom P, Lustgarten J (2003) Cooperative effect between immunotherapy and antiangiogenic therapy leads to effective tumor rejection in tolerant Her-2/neu mice. Cancer Res 63:5895–5901PubMed
20.
Zurück zum Zitat Cuadros C, Dominguez AL, Lollini PL, Croft M, Mittler RS, Borgstrom P, Lustgarten J (2005) Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti-OX40 and anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice. Int J Cancer 116:934–943PubMedCrossRef Cuadros C, Dominguez AL, Lollini PL, Croft M, Mittler RS, Borgstrom P, Lustgarten J (2005) Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti-OX40 and anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice. Int J Cancer 116:934–943PubMedCrossRef
21.
Zurück zum Zitat Lustgarten J, Dominguez AL, Cuadros C (2004) The CD8 + T cell repertoire against Her-2/neu antigens in neu transgenic mice is of low avidity with antitumor activity. Eur J Immunol 34:752–761PubMedCrossRef Lustgarten J, Dominguez AL, Cuadros C (2004) The CD8 + T cell repertoire against Her-2/neu antigens in neu transgenic mice is of low avidity with antitumor activity. Eur J Immunol 34:752–761PubMedCrossRef
22.
Zurück zum Zitat Rovero S, Amici A, Di Carlo E, Bei R, Nanni P, Quaglino E, Porcedda P, Boggio K, Smorlesi A, Lollini PL et al (2000) DNA vaccination against rat her-2/Neu p185 more effectively inhibits carcinogenesis than transplantable carcinomas in transgenic BALB/c mice. J Immunol 165:5133–5142PubMed Rovero S, Amici A, Di Carlo E, Bei R, Nanni P, Quaglino E, Porcedda P, Boggio K, Smorlesi A, Lollini PL et al (2000) DNA vaccination against rat her-2/Neu p185 more effectively inhibits carcinogenesis than transplantable carcinomas in transgenic BALB/c mice. J Immunol 165:5133–5142PubMed
23.
Zurück zum Zitat Xia J, Tanaka Y, Koido S, Liu C, Mukherjee P, Gendler SJ, Gong J (2003) Prevention of spontaneous breast carcinoma by prophylactic vaccination with dendritic/tumor fusion cells. J Immunol 170:1980–1986PubMed Xia J, Tanaka Y, Koido S, Liu C, Mukherjee P, Gendler SJ, Gong J (2003) Prevention of spontaneous breast carcinoma by prophylactic vaccination with dendritic/tumor fusion cells. J Immunol 170:1980–1986PubMed
24.
Zurück zum Zitat Fontenot J, Rasmussen J, Williams L, Dooley J, Farr A, Rudensky A (2005) Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22:329–341PubMedCrossRef Fontenot J, Rasmussen J, Williams L, Dooley J, Farr A, Rudensky A (2005) Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22:329–341PubMedCrossRef
25.
Zurück zum Zitat Choi BK, Bae JS, Choi EM, Kang WJ, Sakaguchi S, Vinay DS, Kwon BS (2004) 4-1BB-dependent inhibition of immunosuppression by activated CD4 + CD25 + T cells. J Leukoc Biol 75:785–791PubMedCrossRef Choi BK, Bae JS, Choi EM, Kang WJ, Sakaguchi S, Vinay DS, Kwon BS (2004) 4-1BB-dependent inhibition of immunosuppression by activated CD4 + CD25 + T cells. J Leukoc Biol 75:785–791PubMedCrossRef
26.
Zurück zum Zitat Valzasina B, Guiducci C, Dislich H, Killeen N, Weinberg A, Colombo M (2005) Triggering of OX40 (CD134) on CD4(+)CD25 + T cells blocks their inhibitory activity: a novel regulatory role for OX40 and the comparison with GITR. Blood 105:2845–2851PubMedCrossRef Valzasina B, Guiducci C, Dislich H, Killeen N, Weinberg A, Colombo M (2005) Triggering of OX40 (CD134) on CD4(+)CD25 + T cells blocks their inhibitory activity: a novel regulatory role for OX40 and the comparison with GITR. Blood 105:2845–2851PubMedCrossRef
27.
Zurück zum Zitat Noelle RJ, Nowak EC (2010) Cellular sources and immune functions of interleukin-9. Nat Rev Immunol 10:683–687PubMedCrossRef Noelle RJ, Nowak EC (2010) Cellular sources and immune functions of interleukin-9. Nat Rev Immunol 10:683–687PubMedCrossRef
28.
Zurück zum Zitat Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6:1142–1151PubMedCrossRef Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6:1142–1151PubMedCrossRef
29.
Zurück zum Zitat Cooper D, Bansal-Pakala P, Croft M (2002) 4-1BB (CD137) controls the clonal expansion and survival of CD8 T cells in vivo but does not contribute to the development of cytotoxicity. Eur J Immunol 32:521–529PubMedCrossRef Cooper D, Bansal-Pakala P, Croft M (2002) 4-1BB (CD137) controls the clonal expansion and survival of CD8 T cells in vivo but does not contribute to the development of cytotoxicity. Eur J Immunol 32:521–529PubMedCrossRef
30.
Zurück zum Zitat Piconese S, Valzasina B, Colombo MP (2008) OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J Exp Med 205:825–839PubMedCrossRef Piconese S, Valzasina B, Colombo MP (2008) OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J Exp Med 205:825–839PubMedCrossRef
31.
Zurück zum Zitat Piconese S, Pittoni P, Burocchi A, Gorzanelli A, Care A, Tripodo C, Colombo MP (2010) A non-redundant role for OX40 in the competitive fitness of Treg in response to IL-2. Eur J Immunol 40:2902–2913PubMedCrossRef Piconese S, Pittoni P, Burocchi A, Gorzanelli A, Care A, Tripodo C, Colombo MP (2010) A non-redundant role for OX40 in the competitive fitness of Treg in response to IL-2. Eur J Immunol 40:2902–2913PubMedCrossRef
32.
Zurück zum Zitat Ruby CE, Yates MA, Hirschhorn-Cymerman D, Chlebeck P, Wolchok JD, Houghton AN, Offner H, Weinberg AD (2009) Cutting edge: OX40 agonists can drive regulatory T cell expansion if the cytokine milieu is right. J Immunol 183:4853–4857PubMedCrossRef Ruby CE, Yates MA, Hirschhorn-Cymerman D, Chlebeck P, Wolchok JD, Houghton AN, Offner H, Weinberg AD (2009) Cutting edge: OX40 agonists can drive regulatory T cell expansion if the cytokine milieu is right. J Immunol 183:4853–4857PubMedCrossRef
33.
Zurück zum Zitat Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K, Scott ZA, Coyle AJ, Reed JL, Van Snick J et al (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442:997–1002PubMedCrossRef Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K, Scott ZA, Coyle AJ, Reed JL, Van Snick J et al (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442:997–1002PubMedCrossRef
34.
Zurück zum Zitat Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, Martin B, Wilhelm C, Stockinger B (2008) Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9:1341–1346PubMedCrossRef Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, Martin B, Wilhelm C, Stockinger B (2008) Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9:1341–1346PubMedCrossRef
35.
Zurück zum Zitat Elyaman W, Bradshaw EM, Uyttenhove C, Dardalhon V, Awasthi A, Imitola J, Bettelli E, Oukka M, van Snick J, Renauld JC et al (2009) IL-9 induces differentiation of TH17 cells and enhances function of FoxP3 + natural regulatory T cells. Proc Natl Acad Sci USA 106:12885–12890PubMedCrossRef Elyaman W, Bradshaw EM, Uyttenhove C, Dardalhon V, Awasthi A, Imitola J, Bettelli E, Oukka M, van Snick J, Renauld JC et al (2009) IL-9 induces differentiation of TH17 cells and enhances function of FoxP3 + natural regulatory T cells. Proc Natl Acad Sci USA 106:12885–12890PubMedCrossRef
36.
Zurück zum Zitat Fukushima A, Yamaguchi T, Ishida W, Fukata K, Mittler RS, Yagita H, Ueno H (2005) Engagement of 4-1BB inhibits the development of experimental allergic conjunctivitis in mice. J Immunol 175:4897–4903PubMed Fukushima A, Yamaguchi T, Ishida W, Fukata K, Mittler RS, Yagita H, Ueno H (2005) Engagement of 4-1BB inhibits the development of experimental allergic conjunctivitis in mice. J Immunol 175:4897–4903PubMed
37.
Zurück zum Zitat Sun Y, Blink SE, Liu W, Lee Y, Chen B, Solway J, Weinstock J, Chen L, Fu YX (2006) Inhibition of Th2-mediated allergic airway inflammatory disease by CD137 costimulation. J Immunol 177:814–821PubMed Sun Y, Blink SE, Liu W, Lee Y, Chen B, Solway J, Weinstock J, Chen L, Fu YX (2006) Inhibition of Th2-mediated allergic airway inflammatory disease by CD137 costimulation. J Immunol 177:814–821PubMed
38.
Zurück zum Zitat Rochman Y, Spolski R, Leonard WJ (2009) New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol 9:480–490PubMedCrossRef Rochman Y, Spolski R, Leonard WJ (2009) New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol 9:480–490PubMedCrossRef
39.
Zurück zum Zitat Yao Z, Kanno Y, Kerenyi M, Stephens G, Durant L, Watford WT, Laurence A, Robinson GW, Shevach EM, Moriggl R et al (2007) Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109:4368–4375PubMedCrossRef Yao Z, Kanno Y, Kerenyi M, Stephens G, Durant L, Watford WT, Laurence A, Robinson GW, Shevach EM, Moriggl R et al (2007) Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109:4368–4375PubMedCrossRef
40.
Zurück zum Zitat Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA (2007) IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3 + regulatory T cells. J Immunol 178:280–290PubMed Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA (2007) IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3 + regulatory T cells. J Immunol 178:280–290PubMed
41.
Zurück zum Zitat Townsend JM, Fallon GP, Matthews JD, Smith P, Jolin EH, McKenzie NA (2000) IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity 13:573–583PubMedCrossRef Townsend JM, Fallon GP, Matthews JD, Smith P, Jolin EH, McKenzie NA (2000) IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity 13:573–583PubMedCrossRef
42.
Zurück zum Zitat Sharma S, Dominguez AL, Hoelzinger DB, Lustgarten J (2008) CpG-ODN but not other TLR-ligands restore the antitumor responses in old mice: the implications for vaccinations in the aged. Cancer Immunol Immunother 57:549–561PubMedCrossRef Sharma S, Dominguez AL, Hoelzinger DB, Lustgarten J (2008) CpG-ODN but not other TLR-ligands restore the antitumor responses in old mice: the implications for vaccinations in the aged. Cancer Immunol Immunother 57:549–561PubMedCrossRef
43.
Zurück zum Zitat Eller K, Wolf D, Huber JM, Metz M, Mayer G, McKenzie AN, Maurer M, Rosenkranz AR, Wolf AM (2011) IL-9 production by regulatory T cells recruits mast cells that are essential for regulatory T cell-induced immune suppression. J Immunol 186:83–91PubMedCrossRef Eller K, Wolf D, Huber JM, Metz M, Mayer G, McKenzie AN, Maurer M, Rosenkranz AR, Wolf AM (2011) IL-9 production by regulatory T cells recruits mast cells that are essential for regulatory T cell-induced immune suppression. J Immunol 186:83–91PubMedCrossRef
44.
Zurück zum Zitat Nowak EC, Weaver CT, Turner H, Begum-Haque S, Becher B, Schreiner B, Coyle AJ, Kasper LH, Noelle RJ (2009) IL-9 as a mediator of Th17-driven inflammatory disease. J Exp Med 206:1653–1660PubMedCrossRef Nowak EC, Weaver CT, Turner H, Begum-Haque S, Becher B, Schreiner B, Coyle AJ, Kasper LH, Noelle RJ (2009) IL-9 as a mediator of Th17-driven inflammatory disease. J Exp Med 206:1653–1660PubMedCrossRef
45.
Zurück zum Zitat White B, Leon F, White W, Robbie G (2009) Two first-in-human, open-label, phase I dose-escalation safety trials of MEDI-528, a monoclonal antibody against interleukin-9, in healthy adult volunteers. Clin Ther 31:728–740PubMedCrossRef White B, Leon F, White W, Robbie G (2009) Two first-in-human, open-label, phase I dose-escalation safety trials of MEDI-528, a monoclonal antibody against interleukin-9, in healthy adult volunteers. Clin Ther 31:728–740PubMedCrossRef
Metadaten
Titel
Signals through 4-1BB inhibit T regulatory cells by blocking IL-9 production enhancing antitumor responses
verfasst von
Shannon E. Smith
Dominique B. Hoelzinger
Ana Lucia Dominguez
Jacques Van Snick
Joseph Lustgarten
Publikationsdatum
01.12.2011
Verlag
Springer-Verlag
Erschienen in
Cancer Immunology, Immunotherapy / Ausgabe 12/2011
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-011-1075-6

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