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Erschienen in: Cancer Immunology, Immunotherapy 5/2013

01.05.2013 | Original article

CD39 is highly involved in mediating the suppression activity of tumor-infiltrating CD8+ T regulatory lymphocytes

verfasst von: Alessia Parodi, Florinda Battaglia, Francesca Kalli, Francesca Ferrera, Giuseppina Conteduca, Samuele Tardito, Silvia Stringara, Federico Ivaldi, Simone Negrini, Giacomo Borgonovo, Alchiede Simonato, Paolo Traverso, Giorgio Carmignani, Daniela Fenoglio, Gilberto Filaci

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 5/2013

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Abstract

CD39 is an ectoenzyme, present on different immune cell subsets, which mediates immunosuppressive functions catalyzing ATP degradation. It is not known whether CD39 is expressed and implicated in the activity of CD8+ regulatory T lymphocytes (Treg). In this study, CD39 expression and function was analyzed in both CD8+ and CD4+CD25hi Treg from the peripheral blood of healthy donors as well as from tumor specimens. CD39 was found expressed by both CD8+ (from the majority of healthy donors and tumor patients) and CD4+CD25hi Treg, and CD39 expression correlated with suppression activity mediated by CD8+ Treg. Importantly, CD39 counteraction remarkably inhibited the suppression activity of CD8+ Treg (both from peripheral blood and tumor microenvironment) suggesting that CD39-mediated inhibition constitutes a prevalent hallmark of their function. Collectively, these findings, unveiling a new mechanism of action for CD8+ Treg, provide new knowledge on intratumoral molecular pathways related to tumor immune escape, which could be exploited in the future for designing new biological tools for anticancer immune intervention.
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Literatur
1.
Zurück zum Zitat Maliszewski CR, Delespesse GJ, Schoenborn MA, Armitage RJ, Fanslow WC, Nakajima T, Baker E, Sutherland GR, Poindexter K, Birks C (1994) The CD39 lymphoid cell activation antigen. Molecular cloning and structural characterization. J Immunol 153:3574–3583PubMed Maliszewski CR, Delespesse GJ, Schoenborn MA, Armitage RJ, Fanslow WC, Nakajima T, Baker E, Sutherland GR, Poindexter K, Birks C (1994) The CD39 lymphoid cell activation antigen. Molecular cloning and structural characterization. J Immunol 153:3574–3583PubMed
2.
Zurück zum Zitat Mizumoto N, Kumamoto T, Robson SC, Sévigny J, Matsue H, Enjyoji K, Takashima A (2002) CD39 is the dominant Langerhans cell-associated ecto-NTPDase: modulatory roles in inflammation and immune responsiveness. Nat Med 8:358–365PubMedCrossRef Mizumoto N, Kumamoto T, Robson SC, Sévigny J, Matsue H, Enjyoji K, Takashima A (2002) CD39 is the dominant Langerhans cell-associated ecto-NTPDase: modulatory roles in inflammation and immune responsiveness. Nat Med 8:358–365PubMedCrossRef
3.
Zurück zum Zitat Airas L, Hellman J, Salmi M, Bono P, Puurunen T, Smith DJ, Jalkanen S (1995) CD73 is involved in lymphocyte binding to the endothelium: characterization of lymphocyte-vascular adhesion protein 2 identifies it as CD73. J Exp Med 182:1603–1608PubMedCrossRef Airas L, Hellman J, Salmi M, Bono P, Puurunen T, Smith DJ, Jalkanen S (1995) CD73 is involved in lymphocyte binding to the endothelium: characterization of lymphocyte-vascular adhesion protein 2 identifies it as CD73. J Exp Med 182:1603–1608PubMedCrossRef
4.
Zurück zum Zitat Stagg J, Smyth MJ (2010) Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29:5346–5358PubMedCrossRef Stagg J, Smyth MJ (2010) Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29:5346–5358PubMedCrossRef
5.
Zurück zum Zitat Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Höpner S, Centonze D, Bernardi G, Dell’Acqua ML, Rossini PM, Battistini L, Rötzschke O, Falk K (2007) Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110:1225–1232PubMedCrossRef Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Höpner S, Centonze D, Bernardi G, Dell’Acqua ML, Rossini PM, Battistini L, Rötzschke O, Falk K (2007) Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110:1225–1232PubMedCrossRef
6.
Zurück zum Zitat Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, Robson SC (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204:1257–1265PubMedCrossRef Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, Robson SC (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204:1257–1265PubMedCrossRef
7.
Zurück zum Zitat Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101:455–458PubMedCrossRef Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101:455–458PubMedCrossRef
8.
Zurück zum Zitat Gershon RK, Kondo K (1971) Infectious immunological tolerance. Immunology 21:903–914PubMed Gershon RK, Kondo K (1971) Infectious immunological tolerance. Immunology 21:903–914PubMed
9.
Zurück zum Zitat Moller G (1988) Do suppressor T cells exist? Scand. J Immunol 27:247–250 Moller G (1988) Do suppressor T cells exist? Scand. J Immunol 27:247–250
10.
Zurück zum Zitat Filaci G, Fenoglio D, Indiveri F (2011) CD8(+) T regulatory/suppressor cells and their relationships with autoreactivity and autoimmunity. Autoimmunity 44:51–57PubMedCrossRef Filaci G, Fenoglio D, Indiveri F (2011) CD8(+) T regulatory/suppressor cells and their relationships with autoreactivity and autoimmunity. Autoimmunity 44:51–57PubMedCrossRef
11.
Zurück zum Zitat Kim HJ, Cantor H (2011) Regulation of self-tolerance by Qa-1-restricted CD8(+) regulatory T cells. Semin Immunol 23:446–452PubMedCrossRef Kim HJ, Cantor H (2011) Regulation of self-tolerance by Qa-1-restricted CD8(+) regulatory T cells. Semin Immunol 23:446–452PubMedCrossRef
12.
Zurück zum Zitat Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6:295–307PubMedCrossRef Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6:295–307PubMedCrossRef
13.
14.
Zurück zum Zitat Filaci G, Fenoglio D, Fravega M, Ansaldo G, Borgonovo G, Traverso P, Villaggio B, Ferrera A, Kunkl A, Rizzi M, Ferrera F, Balestra P, Ghio M, Contini P, Setti M, Olive D, Azzarone B, Carmignani G, Ravetti JL, Torre G, Indiveri F (2007) T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. J Immunol 179:4323–4334PubMed Filaci G, Fenoglio D, Fravega M, Ansaldo G, Borgonovo G, Traverso P, Villaggio B, Ferrera A, Kunkl A, Rizzi M, Ferrera F, Balestra P, Ghio M, Contini P, Setti M, Olive D, Azzarone B, Carmignani G, Ravetti JL, Torre G, Indiveri F (2007) T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. J Immunol 179:4323–4334PubMed
15.
Zurück zum Zitat Wang RF (2008) CD8+ regulatory T cells, their suppressive mechanisms, and regulation in cancer. Hum Immunol 69:811–814PubMedCrossRef Wang RF (2008) CD8+ regulatory T cells, their suppressive mechanisms, and regulation in cancer. Hum Immunol 69:811–814PubMedCrossRef
16.
Zurück zum Zitat Andersen MH, Sørensen RB, Brimnes MK, Svane IM, Becker JC, Straten P (2009) Identification of heme oxygenase-1-specific regulatory CD8+ T cells in cancer patients. J Clin Invest 119:2245–2256PubMedCrossRef Andersen MH, Sørensen RB, Brimnes MK, Svane IM, Becker JC, Straten P (2009) Identification of heme oxygenase-1-specific regulatory CD8+ T cells in cancer patients. J Clin Invest 119:2245–2256PubMedCrossRef
17.
Zurück zum Zitat Jarnicki AG, Lysaght J, Todryk S, Mills KM (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 cells. J Immunol 177:896–904PubMed Jarnicki AG, Lysaght J, Todryk S, Mills KM (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 cells. J Immunol 177:896–904PubMed
18.
Zurück zum Zitat Kiniwa Y, Miyahara Y, Wang HY, Peng W, Peng G, Wheeler TM, Thompson TC, Old LJ, Wang RF (2007) CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res 13:6947–6958PubMedCrossRef Kiniwa Y, Miyahara Y, Wang HY, Peng W, Peng G, Wheeler TM, Thompson TC, Old LJ, Wang RF (2007) CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res 13:6947–6958PubMedCrossRef
19.
Zurück zum Zitat Chaput N, Louafi S, Bardier A, Charlotte F, Vaillant JC, Ménégaux F, Rosenzwajg M, Lemoine F, Klatzmann D, Taieb J (2009) Identification of CD8+ CD25+ Foxp3+ suppressive T cells in colorectal cancer tissue. Gut 58:520–529PubMedCrossRef Chaput N, Louafi S, Bardier A, Charlotte F, Vaillant JC, Ménégaux F, Rosenzwajg M, Lemoine F, Klatzmann D, Taieb J (2009) Identification of CD8+ CD25+ Foxp3+ suppressive T cells in colorectal cancer tissue. Gut 58:520–529PubMedCrossRef
20.
Zurück zum Zitat Chen KJ, Lin SZ, Zhou L, Xie HY, Zhou WH, Taki-Eldin A, Zheng SS (2011) Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis. PLoS ONE 6:e24671PubMedCrossRef Chen KJ, Lin SZ, Zhou L, Xie HY, Zhou WH, Taki-Eldin A, Zheng SS (2011) Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis. PLoS ONE 6:e24671PubMedCrossRef
21.
Zurück zum Zitat Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, Santarlasci V, Serni S, Cosmi L, Maggi L, Angeli R, Mazzinghi B, Romagnani P, Maggi E, Carini M, Romagnani S, Annunziato F (2010) Frequency of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma. BJU Int 107:1500–1506PubMedCrossRef Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, Santarlasci V, Serni S, Cosmi L, Maggi L, Angeli R, Mazzinghi B, Romagnani P, Maggi E, Carini M, Romagnani S, Annunziato F (2010) Frequency of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma. BJU Int 107:1500–1506PubMedCrossRef
22.
Zurück zum Zitat Raghavan S, Quiding-Järbrink M (2011) Regulatory T cells in gastrointestinal tumors. Expert Rev Gastroenterol Hepatol 5:489–501PubMedCrossRef Raghavan S, Quiding-Järbrink M (2011) Regulatory T cells in gastrointestinal tumors. Expert Rev Gastroenterol Hepatol 5:489–501PubMedCrossRef
23.
Zurück zum Zitat Tao H, Mimura Y, Aoe K, Kobayashi S, Yamamoto H, Matsuda E, Okabe K, Matsumoto T, Sugi K, Ueoka H (2012) Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung Cancer 75:95–101PubMedCrossRef Tao H, Mimura Y, Aoe K, Kobayashi S, Yamamoto H, Matsuda E, Okabe K, Matsumoto T, Sugi K, Ueoka H (2012) Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung Cancer 75:95–101PubMedCrossRef
24.
Zurück zum Zitat Liu F, Lang R, Zhao J, Zhang X, Pringle GA, Fan Y, Yin D, Gu F, Yao Z, Fu L (2011) CD8+ cytotoxic T cell and FOXP3+ regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat 130:645–655PubMedCrossRef Liu F, Lang R, Zhao J, Zhang X, Pringle GA, Fan Y, Yin D, Gu F, Yao Z, Fu L (2011) CD8+ cytotoxic T cell and FOXP3+ regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat 130:645–655PubMedCrossRef
25.
Zurück zum Zitat Nishikawa H, Jager E, Ritter G, Old LJ, Gnjatic S (2005) CD4+ CD25+ regulatory T cells control the induction of antigen-specific CD4+ helper T cell responses in cancer patients. Blood 106:1008–1011PubMedCrossRef Nishikawa H, Jager E, Ritter G, Old LJ, Gnjatic S (2005) CD4+ CD25+ regulatory T cells control the induction of antigen-specific CD4+ helper T cell responses in cancer patients. Blood 106:1008–1011PubMedCrossRef
26.
Zurück zum Zitat Nishikawa H, Sakaguchi S (2010) Regulatory T cells in tumor immunity. Int J Cancer 127:759–767PubMed Nishikawa H, Sakaguchi S (2010) Regulatory T cells in tumor immunity. Int J Cancer 127:759–767PubMed
27.
Zurück zum Zitat Shevach EM (2002) CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:389–400PubMed Shevach EM (2002) CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:389–400PubMed
28.
Zurück zum Zitat Sakaguchi S (2004) Naturally arising CD4+ regulatory T cells for immunologic selftolerance and negative control of immune responses. Annu Rev Immunol 22:531–562PubMedCrossRef Sakaguchi S (2004) Naturally arising CD4+ regulatory T cells for immunologic selftolerance and negative control of immune responses. Annu Rev Immunol 22:531–562PubMedCrossRef
29.
Zurück zum Zitat Künzli BM, Bernlochner MI, Rath S, Käser S, Csizmadia E, Enjyoji K, Cowan P, d’Apice A, Dwyer K, Rosenberg R, Perren A, Friess H, Maurer CA, Robson SC (2011) Impact of CD39 and purinergic signalling on the growth and metastasis of colorectal cancer. Purinergic Signal 7:231–241PubMedCrossRef Künzli BM, Bernlochner MI, Rath S, Käser S, Csizmadia E, Enjyoji K, Cowan P, d’Apice A, Dwyer K, Rosenberg R, Perren A, Friess H, Maurer CA, Robson SC (2011) Impact of CD39 and purinergic signalling on the growth and metastasis of colorectal cancer. Purinergic Signal 7:231–241PubMedCrossRef
30.
Zurück zum Zitat Mandapathil M, Whiteside TL (2011) Targeting human inducible regulatory T cells (Tr1) in patients with cancer: blocking of adenosine-prostaglandin E(2) cooperation. Expert Opin Biol Ther 11:1203–1214PubMedCrossRef Mandapathil M, Whiteside TL (2011) Targeting human inducible regulatory T cells (Tr1) in patients with cancer: blocking of adenosine-prostaglandin E(2) cooperation. Expert Opin Biol Ther 11:1203–1214PubMedCrossRef
31.
Zurück zum Zitat Filaci G, Fravega M, Negrini S, Procopio F, Fenoglio D, Rizzi M, Brenci S, Contini P, Olive D, Ghio M, Setti M, Accolla RS, Puppo F, Indiveri F (2004) Non-antigen specific CD8+ T suppressor lymphocytes originate from CD8+ CD28- T cells and inhibit both T-cell proliferation and CTL function. Hum Immunol 65:142–156PubMedCrossRef Filaci G, Fravega M, Negrini S, Procopio F, Fenoglio D, Rizzi M, Brenci S, Contini P, Olive D, Ghio M, Setti M, Accolla RS, Puppo F, Indiveri F (2004) Non-antigen specific CD8+ T suppressor lymphocytes originate from CD8+ CD28- T cells and inhibit both T-cell proliferation and CTL function. Hum Immunol 65:142–156PubMedCrossRef
32.
Zurück zum Zitat Fenoglio D, Ferrera F, Fravega M, Balestra P, Battaglia F, Proietti M, Andrei C, Olive D, Antonio LC, Indiveri F, Filaci G (2008) Advancements on phenotypic and functional characterization of non-antigen-specific CD8+ CD28- regulatory T cells. Hum Immunol 69:745–750PubMedCrossRef Fenoglio D, Ferrera F, Fravega M, Balestra P, Battaglia F, Proietti M, Andrei C, Olive D, Antonio LC, Indiveri F, Filaci G (2008) Advancements on phenotypic and functional characterization of non-antigen-specific CD8+ CD28- regulatory T cells. Hum Immunol 69:745–750PubMedCrossRef
33.
Zurück zum Zitat Sallusto F, Lenig D, Förster R, Lipp M, Lanzavecchia A (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401:708–712PubMedCrossRef Sallusto F, Lenig D, Förster R, Lipp M, Lanzavecchia A (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401:708–712PubMedCrossRef
34.
Zurück zum Zitat Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329–341PubMedCrossRef Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329–341PubMedCrossRef
35.
Zurück zum Zitat Filaci G, Bacilieri S, Fravega M, Monetti M, Contini P, Ghio M, Setti M, Puppo F, Indiveri F (2001) Impairment of CD8+ T suppressor cell function in patients with active systemic lupus erythematosus. J Immunol 166:6452–6457PubMed Filaci G, Bacilieri S, Fravega M, Monetti M, Contini P, Ghio M, Setti M, Puppo F, Indiveri F (2001) Impairment of CD8+ T suppressor cell function in patients with active systemic lupus erythematosus. J Immunol 166:6452–6457PubMed
36.
Zurück zum Zitat Mocellin S, Panelli MC, Wang E, Nagorsen D, Marincola FM (2003) The dual role of IL-10. Trends Immunol 24:36–43CrossRef Mocellin S, Panelli MC, Wang E, Nagorsen D, Marincola FM (2003) The dual role of IL-10. Trends Immunol 24:36–43CrossRef
37.
Zurück zum Zitat Schoenborn JR, Wilson CB (2007) Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96:41–101PubMedCrossRef Schoenborn JR, Wilson CB (2007) Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96:41–101PubMedCrossRef
38.
Zurück zum Zitat Schuett H, Luchtefeld M, Grothusen C, Grote K, Schieffer B (2009) How much is too much? Interleukin-6 and its signalling in atherosclerosis. Thromb Haemost 102:215–222PubMed Schuett H, Luchtefeld M, Grothusen C, Grote K, Schieffer B (2009) How much is too much? Interleukin-6 and its signalling in atherosclerosis. Thromb Haemost 102:215–222PubMed
Metadaten
Titel
CD39 is highly involved in mediating the suppression activity of tumor-infiltrating CD8+ T regulatory lymphocytes
verfasst von
Alessia Parodi
Florinda Battaglia
Francesca Kalli
Francesca Ferrera
Giuseppina Conteduca
Samuele Tardito
Silvia Stringara
Federico Ivaldi
Simone Negrini
Giacomo Borgonovo
Alchiede Simonato
Paolo Traverso
Giorgio Carmignani
Daniela Fenoglio
Gilberto Filaci
Publikationsdatum
01.05.2013
Verlag
Springer-Verlag
Erschienen in
Cancer Immunology, Immunotherapy / Ausgabe 5/2013
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-013-1392-z

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