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01-05-2013 | Original article

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

Authors: 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

Published in: Cancer Immunology, Immunotherapy | Issue 5/2013

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+CD25^hi 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+CD25^hi 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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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

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

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

Stagg J, Smyth MJ (2010) Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29:5346–5358PubMedCrossRef

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

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

Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101:455–458PubMedCrossRef

Gershon RK, Kondo K (1971) Infectious immunological tolerance. Immunology 21:903–914PubMed

Moller G (1988) Do suppressor T cells exist? Scand. J Immunol 27:247–250

10.

Filaci G, Fenoglio D, Indiveri F (2011) CD8(+) T regulatory/suppressor cells and their relationships with autoreactivity and autoimmunity. Autoimmunity 44:51–57PubMedCrossRef

11.

Kim HJ, Cantor H (2011) Regulation of self-tolerance by Qa-1-restricted CD8(+) regulatory T cells. Semin Immunol 23:446–452PubMedCrossRef

12.

Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6:295–307PubMedCrossRef

13.

Wang HY, Wang RF (2007) Regulatory T cells and cancer. Curr Opin Immunol 19:217–223PubMedCrossRef

14.

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.

Wang RF (2008) CD8+ regulatory T cells, their suppressive mechanisms, and regulation in cancer. Hum Immunol 69:811–814PubMedCrossRef

16.

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.

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.

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.

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.

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.

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.

Raghavan S, Quiding-Järbrink M (2011) Regulatory T cells in gastrointestinal tumors. Expert Rev Gastroenterol Hepatol 5:489–501PubMedCrossRef

23.

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.

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.

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.

Nishikawa H, Sakaguchi S (2010) Regulatory T cells in tumor immunity. Int J Cancer 127:759–767PubMed

27.

Shevach EM (2002) CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:389–400PubMed

28.

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.

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.

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.

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.

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.

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.

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.

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.

Mocellin S, Panelli MC, Wang E, Nagorsen D, Marincola FM (2003) The dual role of IL-10. Trends Immunol 24:36–43CrossRef

37.

Schoenborn JR, Wilson CB (2007) Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96:41–101PubMedCrossRef

38.

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

Title: CD39 is highly involved in mediating the suppression activity of tumor-infiltrating CD8+ T regulatory lymphocytes
Authors: 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
Publication date: 01-05-2013
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 5/2013
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-013-1392-z

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