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Oncoimmunology pp 483-506 | Cite as

Strategies to Reduce Intratumoral Regulatory T Cells

  • C. Maherzi
  • F. Onodi
  • E. Tartour
  • M. Terme
  • C. TanchotEmail author
Chapter

Abstract

Regulatory T cells (Tregs) include diverse subsets of immunosuppressive cells that play a critical role in self-tolerance and immune homeostasis. Due to their immunosuppressive capacities, Tregs are able to suppress antitumoral responses through several mechanisms and therefore enhance tumor escape and progression.

Tregs are characterized by the expression of forkhead box P3 (FoxP3), which is essential for their development and function. While mouse Tregs express constitutively FoxP3, human Tregs do not necessarily do. Moreover, activated human conventional T cells (Tconv) transiently express intermediate levels of FoxP3. That is why the characterization and identification of human Tregs is more complex and involves more combined markers. Currently, in human studies, Tregs are identified by flow cytometry as CD3+ CD4+ CD25high CD127low cells.

Keywords

Cancer Regulatory T cells Immunosuppression Tumor microenvironment Tumor-infiltrating T lymphocytes Therapeutic strategies 

Abbreviations

A2aR

Adenosine 2a receptor

A2bR

Adenosine 2b receptor

ADCC

Antibody-dependent cell-mediated cytotoxicity

ADCP

Antibody-dependent cellular phagocytosis

APC

Antigen-presenting cell

ATLL

Adult T-cell leukemia–lymphoma

BCG

Bacille Calmette–Guérin

Bevacizumab

Anti-VEGF mAb

CCR4

C-C motif chemokine receptor 4

CCL22

C-C motif chemokine ligand 22

CEA

Carcinoembryonic antigen

CTCL

Cutaneous T-cell lymphoma

CTL

Cytotoxic T lymphocyte

CTLA-4

Cytotoxic T lymphocyte antigen-4

CTX

Cyclophosphamide

CXCL12

CXC chemokine ligand 12

CTL

Cytotoxic CD8+ T cell

CDC

Complement-dependent cytotoxicity

DC

Dendritic cell

DD

Denileukin diftitox

DgA

Deglycosylated ricin A

EGFR

Epidermal growth factor receptor

eTreg

Effector Tregs

FDA

Food and Drug Administration

FDB

Fludarabine

FcγR

Fcγ receptor

FoxP3

Forkhead box P3

GITR

Glucocorticoid-induced TNF-related protein

GITRL

GITR ligand

HNSCC

Head and neck squamous cell carcinoma

ICOS

Inducible costimulator

IDO

Indoleamine 2,3-dioxygenase

IL-2

Interleukin-2

IL-2R

IL-2 receptor

LAG-3

Lymphocyte activation gene-3

mAb

Monoclonal antibody

MCP-1

Monocyte chemoattractant protein-1

mCRPC

Metastatic castration-resistant prostate cancer

MDSC

Myeloid-derived suppressor cell

MEDI4736/atezolizumab/ durvalumab

Anti-PD-L1 mAbs

mRCC

Metastatic renal cell cancer

NIR

Near-infrared

NK

Natural killer cell

OS

Overall survival

OX40

CD134

OX40L

OX40 ligand

PD-1

Programmed death-1

PF-05082566

4-1BB agonist mAb

Pembrolizumab

Anti- PD-1 mAb

PTCL

Peripheral T-cell lymphoma

PTX

Paclitaxel

RCC

Renal cell carcinoma

Rituximab

Anti-CD20 mAb

SDF-1

Stromal cell-derived factor-1

Tconv

Conventional T cells

Teff

Effector T cell

TI

Tumor-infiltrating

TIL

Tumor-infiltrating lymphocyte

TME

Tumor microenvironment

TNF

Tumor necrosis factor

Treg

Regulatory T cell

Tremelimumab

Anti-CTLA-4 mAb

VEGF-A

Vascular endothelial growth factor-A

Notes

Acknowledgments

This work was supported by the Agence Nationale de la Recherche (ANR), the Ligue contre le cancer, the Association des Gastroentérologues Oncologues, SIRIC CARPEM, Labex Onco-Immunology, and INCA.

References

  1. 1.
    Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2016;27(1):109–18. doi: 10.1038/cr.2016.151.PubMedCrossRefGoogle Scholar
  2. 2.
    Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531–62.PubMedCrossRefGoogle Scholar
  4. 4.
    Pillai V, Ortega SB, Wang CK, Karandikar NJ. Transient regulatory T-cells: a state attained by all activated human T-cells. Clin Immunol. 2007;123:18–29.PubMedCrossRefGoogle Scholar
  5. 5.
    Rodríguez-Perea AL, Arcia ED, Rueda CM, Velilla PA. Phenotypical characterization of regulatory T cells in humans and rodents. Clin Exp Immunol. 2016;185:281–91.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Liu W, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203:1701–11.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Lages CS, et al. Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation. J Immunol. 2008;1950(181):1835–48.CrossRefGoogle Scholar
  8. 8.
    Tang AL, et al. CTLA4 expression is an indicator and regulator of steady-state CD4+ FoxP3+ T cell homeostasis. J Immunol. 2008;1950(181):1806–13.CrossRefGoogle Scholar
  9. 9.
    Raimondi G, Shufesky WJ, Tokita D, Morelli AE, Thomson AW. Regulated compartmentalization of programmed cell death-1 discriminates CD4+CD25+ resting regulatory T cells from activated T cells. J Immunol. 2006;1950(176):2808–16.CrossRefGoogle Scholar
  10. 10.
    Huang C-T, et al. Role of LAG-3 in regulatory T cells. Immunity. 2004;21:503–13.PubMedCrossRefGoogle Scholar
  11. 11.
    McHugh RS, et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity. 2002;16:311–23.PubMedCrossRefGoogle Scholar
  12. 12.
    Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol. 2002;3:135–42.PubMedCrossRefGoogle Scholar
  13. 13.
    Takeda I, et al. Distinct roles for the OX40-OX40 ligand interaction in regulatory and nonregulatory T cells. J Immunol. 2004;1950(172):3580–9.CrossRefGoogle Scholar
  14. 14.
    Gobert M, et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res. 2009;69:2000–9.Google Scholar
  15. 15.
    Borsellino G, et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood. 2007;110:1225–32.PubMedCrossRefGoogle Scholar
  16. 16.
    Kobie JJ, et al. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5′-adenosine monophosphate to adenosine. J Immunol. 2006;1950(177):6780–6.CrossRefGoogle Scholar
  17. 17.
    Asseman C, Mauze S, Leach MW, Coffman RL, Powrie F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med. 1999;190:995–1004.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Joetham A, et al. Naturally occurring lung CD4(+)CD25(+) T cell regulation of airway allergic responses depends on IL-10 induction of TGF-beta. J Immunol. 2007;1950(178):1433–42.CrossRefGoogle Scholar
  19. 19.
    Collison LW, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450:566–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Grossman WJ, et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity. 2004;21:589–601.PubMedCrossRefGoogle Scholar
  21. 21.
    Mandapathil M, Lang S, Gorelik E, Whiteside TL. Isolation of functional human regulatory T cells (Treg) from the peripheral blood based on the CD39 expression. J Immunol Methods. 2009;346:55–63.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Read S, Malmström V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000;192:295–302.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Yan Z, Garg SK, Banerjee R. Regulatory T cells interfere with glutathione metabolism in dendritic cells and T cells. J Biol Chem. 2010;285:41525–32.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010;11:7–13.PubMedCrossRefGoogle Scholar
  25. 25.
    Liyanage UK, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169:2756–61.PubMedCrossRefGoogle Scholar
  26. 26.
    Kobayashi N, et al. FOXP3(+) regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res. 2007;13:902–11.PubMedCrossRefGoogle Scholar
  27. 27.
    Woo EY, et al. Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 2001;61:4766–72.PubMedGoogle Scholar
  28. 28.
    Curiel TJ, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Carreras J, et al. High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood. 2006;108:2957–64.PubMedCrossRefGoogle Scholar
  30. 30.
    Badoual C, et al. Prognostic value of tumor-infiltrating CD4(+) T-cell subpopulations in head and neck cancers. Clin Cancer Res. 2006;12:465–72.PubMedCrossRefGoogle Scholar
  31. 31.
    Grabenbauer GG, Lahmer G, Distel L, Niedobitek G. Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma. Clin Cancer Res. 2006;12:3355–60.PubMedCrossRefGoogle Scholar
  32. 32.
    Faget J, et al. Early detection of tumor cells by innate immune cells leads to T-reg recruitment through CCL22 production by tumor cells. Cancer Res. 2011;71:6143–52.PubMedCrossRefGoogle Scholar
  33. 33.
    Yan M, et al. Recruitment of regulatory T cells is correlated with hypoxia-induced CXCR4 expression, and is associated with poor prognosis in basal-like breast cancers. Breast Cancer Res. 2011;13:R47.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Bu M, et al. Ovarian carcinoma-infiltrating regulatory T cells were more potent suppressors of CD8(+) T cell inflammation than their peripheral counterparts, a function dependent on TIM3 expression. Tumour Biol. 2016;37:3949–56.PubMedCrossRefGoogle Scholar
  35. 35.
    Chaudhary B, Elkord E. Regulatory T cells in the tumor microenvironment and cancer progression: role and therapeutic targeting. Vaccine. 2016;4(3):28.CrossRefGoogle Scholar
  36. 36.
    Jie H-B, et al. Intratumoral regulatory T cells upregulate immunosuppressive molecules in head and neck cancer patients. Br J Cancer. 2013;109:2629–35.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Pedroza-Gonzalez A, et al. Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer. Hepatology. 2013;57:183–94.PubMedCrossRefGoogle Scholar
  38. 38.
    Strauss L, et al. A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment. Clin Cancer Res. 2007;13:4345–54.PubMedCrossRefGoogle Scholar
  39. 39.
    Pere H, et al. Comprehensive analysis of current approaches to inhibit regulatory T cells in cancer. Oncoimmunology. 2012;1:326–33.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Whiteside TL. The role of regulatory T cells in cancer immunology. ImmunoTargets Ther. 2015;4:159–71.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Colleoni M, et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002;13:73–80.PubMedCrossRefGoogle Scholar
  42. 42.
    El-Arab LRE, Swellam M, El Mahdy MM. Metronomic chemotherapy in metastatic breast cancer: impact on VEGF. J Egypt Natl Cancer Inst. 2012;24:15–22.CrossRefGoogle Scholar
  43. 43.
    Ghiringhelli F, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 2007;56:641–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Lutsiak MEC, et al. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood. 2005;105:2862–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov. 2012;11:215–33.PubMedCrossRefGoogle Scholar
  46. 46.
    Ghiringhelli F, et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol. 2004;34:336–44.PubMedCrossRefGoogle Scholar
  47. 47.
    Ge Y, et al. Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunological effects and clinical outcome. Cancer Immunol Immunother. 2012;61:353–62.PubMedCrossRefGoogle Scholar
  48. 48.
    Walter S, et al. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med. 2012;18:1254–61.PubMedCrossRefGoogle Scholar
  49. 49.
    Podrazil M, et al. Phase I/II clinical trial of dendritic-cell based immunotherapy (DCVAC/PCa) combined with chemotherapy in patients with metastatic, castration-resistant prostate cancer. Oncotarget. 2015;6:18192–205.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Audia S, et al. Increase of CD4+ CD25+ regulatory T cells in the peripheral blood of patients with metastatic carcinoma: a phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+ CD25+ T lymphocytes. Clin Exp Immunol. 2007;150:523–30.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Koumarianou A, et al. The effect of metronomic versus standard chemotherapy on the regulatory to effector T-cell equilibrium in cancer patients. Exp Hematol Oncol. 2014;3:3.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Ellebaek E, et al. Metastatic melanoma patients treated with dendritic cell vaccination, interleukin-2 and metronomic cyclophosphamide: results from a phase II trial. Cancer Immunol Immunother. 2012;61:1791–804.PubMedCrossRefGoogle Scholar
  53. 53.
    Romiti A, et al. Metronomic chemotherapy for cancer treatment: a decade of clinical studies. Cancer Chemother Pharmacol. 2013;72:13–33.PubMedCrossRefGoogle Scholar
  54. 54.
    von Boehmer H, Daniel C. Therapeutic opportunities for manipulating T(Reg) cells in autoimmunity and cancer. Nat Rev Drug Discov. 2013;12:51–63.CrossRefGoogle Scholar
  55. 55.
    Rech AJ, Vonderheide RH. Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Ann N Y Acad Sci. 2009;1174:99–106.PubMedCrossRefGoogle Scholar
  56. 56.
    Waldmann TA. Anti-Tac (daclizumab, Zenapax) in the treatment of leukemia, autoimmune diseases, and in the prevention of allograft rejection: a 25-year personal odyssey. J Clin Immunol. 2007;27:1–18.PubMedCrossRefGoogle Scholar
  57. 57.
    Jacobs JFM, et al. Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients. Clin Cancer Res. 2010;16:5067–78.PubMedCrossRefGoogle Scholar
  58. 58.
    Rech AJ, et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci Transl Med. 2012;4:134ra62.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Attia P, Maker AV, Haworth LR, Rogers-Freezer L, Rosenberg SA. Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma. J Immunother. 2005;1997(28):582–92.CrossRefGoogle Scholar
  60. 60.
    Baur AS, et al. Denileukin diftitox (ONTAK) induces a tolerogenic phenotype in dendritic cells and stimulates survival of resting Treg. Blood. 2013;122:2185–94.PubMedCrossRefGoogle Scholar
  61. 61.
    Duvic M, Talpur R. Optimizing denileukin diftitox (Ontak) therapy. Future Oncol. 2008;4:457–69.PubMedCrossRefGoogle Scholar
  62. 62.
    Foss FM. DAB(389)IL-2 (ONTAK): a novel fusion toxin therapy for lymphoma. Clin Lymphoma. 2000;1:110–116. ; discussion 117.PubMedCrossRefGoogle Scholar
  63. 63.
    Morse MA, et al. Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines. Blood. 2008;112:610–8.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Dannull J, et al. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Investig. 2005;115:3623–33.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Luke JJ, Zha Y, Matijevich K, Gajewski TF. Single dose denileukin diftitox does not enhance vaccine-induced T cell responses or effectively deplete Tregs in advanced melanoma: immune monitoring and clinical results of a randomized phase II trial. J Immunother Cancer. 2016;4:35.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Rasku MA, et al. Transient T cell depletion causes regression of melanoma metastases. J Transl Med. 2008;6:12.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Telang S, et al. Phase II trial of the regulatory T cell-depleting agent, denileukin diftitox, in patients with unresectable stage IV melanoma. BMC Cancer. 2011;11:515.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Mahnke K, et al. Depletion of CD4+CD25+ human regulatory T cells in vivo: kinetics of Treg depletion and alterations in immune functions in vivo and in vitro. Int J Cancer. 2007;120:2723–33.PubMedCrossRefGoogle Scholar
  69. 69.
    Atchison E, et al. A pilot study of denileukin diftitox (DD) in combination with high-dose interleukin-2 (IL-2) for patients with metastatic renal cell carcinoma (RCC). J Immunother. 2010;1997(33):716–22.CrossRefGoogle Scholar
  70. 70.
    Melillo JA, et al. Dendritic cell (DC)-specific targeting reveals Stat3 as a negative regulator of DC function. J Immunol. 2010;1950(184):2638–45.CrossRefGoogle Scholar
  71. 71.
    Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685–711.PubMedCrossRefGoogle Scholar
  72. 72.
    Kreitman RJ, et al. Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J Clin Oncol Off J Am Soc Clin Oncol. 2000;18:1622–36.CrossRefGoogle Scholar
  73. 73.
    Powell DJ, et al. Administration of a CD25-directed immunotoxin, LMB-2, to patients with metastatic melanoma induces a selective partial reduction in regulatory T cells in vivo. J Immunol. 2007;1950(179):4919–28.CrossRefGoogle Scholar
  74. 74.
    Powell DJ, et al. Partial reduction of human FOXP3+ CD4 T cells in vivo after CD25-directed recombinant immunotoxin administration. J Immunother. 2008;1997(31):189–98.CrossRefGoogle Scholar
  75. 75.
    Corthay A. How do regulatory T cells work? Scand J Immunol. 2009;70:326–36.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Sato K, et al. Spatially selective depletion of tumor-associated regulatory T cells with near-infrared photoimmunotherapy. Sci Transl Med. 2016;8:352ra110.PubMedCrossRefGoogle Scholar
  77. 77.
    Miyara M, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30:899–911.PubMedCrossRefGoogle Scholar
  78. 78.
    Sun W, et al. Blockade of MCP-1/CCR4 signaling-induced recruitment of activated regulatory cells evokes an antitumor immune response in head and neck squamous cell carcinoma. Oncotarget. 2016;7:37714–27.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Ito A, et al. Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rgamma(null) mouse model. Cancer Immunol Immunother. 2009;58:1195–206.PubMedCrossRefGoogle Scholar
  80. 80.
    Pere H, et al. A CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens. Blood. 2011;118:4853–62.PubMedCrossRefGoogle Scholar
  81. 81.
    Duvic M, Evans M, Wang C. Mogamulizumab for the treatment of cutaneous T-cell lymphoma: recent advances and clinical potential. Ther Adv Hematol. 2016;7:171–4.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Sugaya M, et al. CCR4 is expressed on infiltrating cells in lesional skin of early mycosis fungoides and atopic dermatitis. J Dermatol. 2015;42:613–5.PubMedCrossRefGoogle Scholar
  83. 83.
    Ogura M, et al. Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32:1157–63.CrossRefGoogle Scholar
  84. 84.
    Vidulich KA, Talpur R, Bassett RL, Duvic M. Overall survival in erythrodermic cutaneous T-cell lymphoma: an analysis of prognostic factors in a cohort of patients with erythrodermic cutaneous T-cell lymphoma. Int J Dermatol. 2009;48:243–52.PubMedCrossRefGoogle Scholar
  85. 85.
    Duvic M, et al. Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma. Blood. 2015;125:1883–9.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Ni X, et al. Reduction of regulatory T cells by Mogamulizumab, a defucosylated anti-CC chemokine receptor 4 antibody, in patients with aggressive/refractory mycosis fungoides and Sézary syndrome. Clin Cancer Res. 2015;21:274–85.PubMedCrossRefGoogle Scholar
  87. 87.
    Wei S, Kryczek I, Zou W. Regulatory T-cell compartmentalization and trafficking. Blood. 2006;108:426–31.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4:540–50.PubMedCrossRefGoogle Scholar
  89. 89.
    Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res. 2010;16:2927–31.PubMedCrossRefGoogle Scholar
  90. 90.
    McConnell AT, et al. The prognostic significance and impact of the CXCR4-CXCR7-CXCL12 axis in primary cutaneous melanoma. Br J Dermatol. 2016;175:1210–20.PubMedCrossRefGoogle Scholar
  91. 91.
    Xue B, et al. Stromal cell-derived factor-1 (SDF-1) enhances cells invasion by αvβ6 integrin-mediated signaling in ovarian cancer. Mol Cell Biochem. 2013;380:177–84.PubMedCrossRefGoogle Scholar
  92. 92.
    Hartmann TN, Burger JA, Glodek A, Fujii N, Burger M. CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells. Oncogene. 2005;24:4462–71.PubMedCrossRefGoogle Scholar
  93. 93.
    Li Y, et al. Co-expression of uPAR and CXCR4 promotes tumor growth and metastasis in small cell lung cancer. Int J Clin Exp Pathol. 2014;7:3771–80.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Yasumoto K, et al. Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer. Cancer Res. 2006;66:2181–7.PubMedCrossRefGoogle Scholar
  95. 95.
    Phillips RJ, et al. The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases. Am J Respir Crit Care Med. 2003;167:1676–86.PubMedCrossRefGoogle Scholar
  96. 96.
    Zhang L, Yeger H, Das B, Irwin MS, Baruchel S. Tissue microenvironment modulates CXCR4 expression and tumor metastasis in neuroblastoma. Neoplasia. 2007;9:36–46.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Yu S, Wang X, Liu G, Zhu X, Chen Y. High level of CXCR4 in triple-negative breast cancer specimens associated with a poor clinical outcome. Acta Med Okayama. 2013;67:369–75.PubMedGoogle Scholar
  98. 98.
    Devine SM, et al. Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin’s lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22:1095–102.CrossRefGoogle Scholar
  99. 99.
    Duda DG, et al. CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies? Clin. Cancer Res. 2011;17:2074–80.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Hassan S, et al. CXCR4 peptide antagonist inhibits primary breast tumor growth, metastasis and enhances the efficacy of anti-VEGF treatment or docetaxel in a transgenic mouse model. Int J Cancer. 2011;129:225–32.PubMedCrossRefGoogle Scholar
  101. 101.
    Shaked Y, et al. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell. 2008;14:263–73.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Singh S, Srivastava SK, Bhardwaj A, Owen LB, Singh AP. CXCL12–CXCR4 signalling axis confers gemcitabine resistance to pancreatic cancer cells: a novel target for therapy. Br J Cancer. 2010;103:1671–9.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Chen Y, et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology. 2015;61:1591–602.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Voron T, et al. Control of the immune response by pro-angiogenic factors. Front Oncol. 2014;4:70.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Gabrilovich DI, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med. 1996;2:1096–103.PubMedCrossRefGoogle Scholar
  106. 106.
    Huang Y, et al. Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF. Blood. 2007;110:624–31.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Terme M, et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 2013;73:539–49.PubMedCrossRefGoogle Scholar
  108. 108.
    Suzuki H, et al. VEGFR2 is selectively expressed by FOXP3high CD4+ Treg. Eur J Immunol. 2010;40:197–203.PubMedCrossRefGoogle Scholar
  109. 109.
    Jaini R, Rayman P, Cohen PA, Finke JH, Tuohy VK. Combination of sunitinib with anti-tumor vaccination inhibits T cell priming and requires careful scheduling to achieve productive immunotherapy. Int J Cancer. 2014;134:1695–705.PubMedCrossRefGoogle Scholar
  110. 110.
    Adotevi O, et al. A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J Immunother. 2010;1997(33):991–8.CrossRefGoogle Scholar
  111. 111.
    Nagai H, et al. Sorafenib prevents escape from host immunity in liver cirrhosis patients with advanced hepatocellular carcinoma. Clin Dev Immunol. 2012;2012:1–8.CrossRefGoogle Scholar
  112. 112.
    Voron T, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015;212:139–48.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Kavanagh B, et al. CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion. Blood. 2008;112:1175–83.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Walker LSK. Treg and CTLA-4: two intertwining pathways to immune tolerance. J Autoimmun. 2013;45:49–57.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Tivol EA, et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3:541–7.PubMedCrossRefGoogle Scholar
  116. 116.
    Waterhouse P, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270:985–8.PubMedCrossRefGoogle Scholar
  117. 117.
    Cross AH, et al. Long-term inhibition of murine experimental autoimmune encephalomyelitis using CTLA-4-fc supports a key role for CD28 costimulation. J Clin Investig. 1995;95:2783–9.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Lühder F, Höglund P, Allison JP, Benoist C, Mathis D. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes. J Exp Med. 1998;187:427–32.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Ménard C, et al. Ctla-4 blockade confers lymphocyte resistance to regulatory T-cells in advanced melanoma: surrogate marker of efficacy of tremelimumab? Clin Cancer Res. 2008;14:5242–9.PubMedCrossRefGoogle Scholar
  120. 120.
    Phan GQ, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100:8372–7.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Hodi FS, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003;100:4712–7.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Takahashi T, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192:303–10.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Weber JS, et al. Ipilimumab increases activated T cells and enhances humoral immunity in patients with advanced melanoma. J. Immunother. 2012;1997(35):89–97.CrossRefGoogle Scholar
  124. 124.
    Tarhini AA, et al. Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS One. 2014;9:e87705.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Maker AV, Attia P, Rosenberg SA. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J. Immunol. 2005;1950(175):7746–54.CrossRefGoogle Scholar
  126. 126.
    Selby MJ, et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res. 2013;1:32–42.PubMedCrossRefGoogle Scholar
  127. 127.
    Simpson TR, et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med. 2013;210:1695–710.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Jie H-B, et al. CTLA-4+ regulatory T cells increased in Cetuximab-treated head and neck cancer patients suppress NK cell cytotoxicity and correlate with poor prognosis. Cancer Res. 2015;75:2200–10.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Romano E, et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci U S A. 2015;112:6140–5.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Reuben JM, et al. Biologic and immunomodulatory events after CTLA-4 blockade with ticilimumab in patients with advanced malignant melanoma. Cancer. 2006;106:2437–44.PubMedCrossRefGoogle Scholar
  131. 131.
    Ribas A, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31:616–22.CrossRefGoogle Scholar
  132. 132.
    Ribas A, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23:8968–77.CrossRefGoogle Scholar
  133. 133.
    Peggs KS, Quezada SA, Korman AJ, Allison JP. Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr Opin Immunol. 2006;18:206–13.PubMedCrossRefGoogle Scholar
  134. 134.
    Krausz LT, et al. GITR-GITRL system, a novel player in shock and inflammation. Sci World J. 2007;7:533–66.CrossRefGoogle Scholar
  135. 135.
    Kanamaru F, et al. Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells. J Immunol. 2004;1950(172):7306–14.CrossRefGoogle Scholar
  136. 136.
    Knee DA, Hewes B, Brogdon JL. Rationale for anti-GITR cancer immunotherapy. Eur J Cancer. 2016;1990(67):1–10.CrossRefGoogle Scholar
  137. 137.
    Côté AL, et al. Stimulation of the glucocorticoid-induced TNF receptor family-related receptor on CD8 T cells induces protective and high-avidity T cell responses to tumor-specific antigens. J Immunol. 2011;186:275–83.PubMedCrossRefGoogle Scholar
  138. 138.
    Ji H, et al. Cutting edge: the natural ligand for glucocorticoid-induced TNF receptor-related protein abrogates regulatory T cell suppression. J Immunol. 2004;1950(172):5823–7.CrossRefGoogle Scholar
  139. 139.
    Bulliard Y, et al. Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J Exp Med. 2013;210:1685–93.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Coe D, et al. Depletion of regulatory T cells by anti-GITR mAb as a novel mechanism for cancer immunotherapy. Cancer Immunol Immunother. 2010;59:1367–77.PubMedCrossRefGoogle Scholar
  141. 141.
    Hu P, et al. Construction and preclinical characterization of Fc-mGITRL for the immunotherapy of cancer. Clin Cancer Res. 2008;14:579–88.PubMedCrossRefGoogle Scholar
  142. 142.
    Kim I-K, et al. Glucocorticoid-induced tumor necrosis factor receptor-related protein co-stimulation facilitates tumor regression by inducing IL-9-producing helper T cells. Nat Med. 2015;21:1010–7.PubMedCrossRefGoogle Scholar
  143. 143.
    Schaer DA, et al. GITR pathway activation abrogates tumor immune suppression through loss of regulatory T-cell lineage stability. Cancer Immunol Res. 2013;1:320–31.PubMedCrossRefGoogle Scholar
  144. 144.
    Turk MJ, et al. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med. 2004;200:771–82.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Cohen AD, et al. Agonist anti-GITR antibody enhances vaccine-induced CD8(+) T-cell responses and tumor immunity. Cancer Res. 2006;66:4904–12.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Lutsiak MEC, Tagaya Y, Adams AJ, Schlom J, Sabzevari H. Tumor-induced impairment of TCR signaling results in compromised functionality of tumor-infiltrating regulatory T cells. J Immunol. 2008;180:5871–81.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Ronchetti S, et al. GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations. Eur J Immunol. 2004;34:613–22.PubMedCrossRefGoogle Scholar
  148. 148.
    Stephens GL, et al. Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J Immunol. 2004;173:5008–20.PubMedCrossRefGoogle Scholar
  149. 149.
    Cohen AD, et al. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS One. 2010;5:e10436.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Stewart RA, et al. Abstract 561: MEDI1873: a novel hexameric GITRL fusion protein with potent agonsitic and immunomodulatory activities in preclinical systems. Cancer Res. 2016;76:561.CrossRefGoogle Scholar
  151. 151.
    Serghides L, et al. Evaluation of OX40 ligand as a costimulator of human antiviral memory CD8 T cell responses: comparison with B7.1 and 4-1BBL. J Immunol. 2005;175:6368–77.PubMedCrossRefGoogle Scholar
  152. 152.
    Ito T, et al. TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med. 2005;202:1213–23.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Zhang Z, et al. Activation of OX40 augments Th17 cytokine expression and antigen-specific uveitis. Am J Pathol. 2010;177:2912–20.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Ishii N, Takahashi T, Soroosh P, Sugamura K. OX40-OX40 ligand interaction in T-cell-mediated immunity and immunopathology. Adv Immunol. 2010;105:63–98.PubMedCrossRefGoogle Scholar
  155. 155.
    Murata K, et al. Impairment of antigen-presenting cell function in mice lacking expression of OX40 ligand. J Exp Med. 2000;191:365–74.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Ohshima Y, et al. Expression and function of OX40 ligand on human dendritic cells. J Immunol. 1997;159:3838–48.PubMedGoogle Scholar
  157. 157.
    Morris A, et al. Induction of anti-mammary cancer immunity by engaging the OX-40 receptor in vivo. Breast Cancer Res Treat. 2001;67:71–80.PubMedCrossRefGoogle Scholar
  158. 158.
    Montler R, et al. OX40, PD-1 and CTLA-4 are selectively expressed on tumor-infiltrating T cells in head and neck cancer. Clin Transl Immunol. 2016;5:e70.CrossRefGoogle Scholar
  159. 159.
    Vetto JT, et al. Presence of the T-cell activation marker OX-40 on tumor infiltrating lymphocytes and draining lymph node cells from patients with melanoma and head and neck cancers. Am J Surg. 1997;174:258–65.PubMedCrossRefGoogle Scholar
  160. 160.
    Linch SN, McNamara MJ, Redmond WL. OX40 agonists and combination immunotherapy: putting the pedal to the metal. Front Oncol. 2015;5:34.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Willoughby J, Griffiths J, Tews I, Cragg MS. OX40: structure and function - what questions remain? Mol Immunol. 2017;83:13–22.PubMedCrossRefGoogle Scholar
  162. 162.
    Croft M. Control of immunity by the TNFR-related molecule OX40 (CD134). Annu Rev Immunol. 2010;28:57–78.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Voo KS, et al. Antibodies targeting human OX40 expand effector T cells and block inducible and natural regulatory T cell function. J Immunol. 2013;191:3641–50.PubMedCrossRefGoogle Scholar
  164. 164.
    Marabelle A, et al. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Investig. 2013;123:2447–63.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Bulliard Y, et al. OX40 engagement depletes intratumoral Tregs via activating FcγRs, leading to antitumor efficacy. Immunol Cell Biol. 2014;92:475–80.PubMedCrossRefGoogle Scholar
  166. 166.
    Aspeslagh S, et al. Rationale for anti-OX40 cancer immunotherapy. Eur J Cancer. 2016;52:50–66.PubMedCrossRefGoogle Scholar
  167. 167.
    Bansal-Pakala P, Jember AG, Croft M. Signaling through OX40 (CD134) breaks peripheral T-cell tolerance. Nat Med. 2001;7:907–12.PubMedCrossRefGoogle Scholar
  168. 168.
    Jensen SM, et al. Signaling through OX40 enhances antitumor immunity. Semin Oncol. 2010;37:524–32.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Redmond WL, Weinberg AD. Targeting OX40 and OX40L for the treatment of autoimmunity and cancer. Crit Rev Immunol. 2007;27:415–36.PubMedCrossRefGoogle Scholar
  170. 170.
    Kjaergaard J, et al. Therapeutic efficacy of OX-40 receptor antibody depends on tumor immunogenicity and anatomic site of tumor growth. Cancer Res. 2000;60:5514–21.PubMedGoogle Scholar
  171. 171.
    Murphy KA, et al. An in vivo immunotherapy screen of costimulatory molecules identifies Fc-OX40L as a potent reagent for the treatment of established murine gliomas. Clin Cancer Res. 2012;18:4657–68.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Piconese S, Valzasina B, Colombo MP. OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J Exp Med. 2008;205:825–39.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Redmond WL, Ruby CE, Weinberg AD. The role of OX40-mediated co-stimulation in T-cell activation and survival. Crit Rev Immunol. 2009;29:187–201.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Sadun RE, et al. Fc-mOX40L fusion protein produces complete remission and enhanced survival in 2 murine tumor models. J Immunother. 2008;1997(31):235–45.CrossRefGoogle Scholar
  175. 175.
    Guo Z, et al. PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer. PLoS One. 2014;9:e89350.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Kitamura N, et al. OX40 costimulation can abrogate Foxp3+ regulatory T cell-mediated suppression of antitumor immunity. Int J Cancer. 2009;125:630–8.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Qian J, et al. Active vaccination with Dickkopf-1 induces protective and therapeutic antitumor immunity in murine multiple myeloma. Blood. 2012;119:161–9.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Curti BD, et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 2013;73:7189–98.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Deaglio S, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007;204:1257–65.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Heine P, et al. The C-terminal cysteine-rich region dictates specific catalytic properties in chimeras of the ectonucleotidases NTPDase1 and NTPDase2. Eur J Biochem. 2001;268:364–73.PubMedCrossRefGoogle Scholar
  181. 181.
    Hunsucker SA, Mitchell BS, Spychala J. The 5′-nucleotidases as regulators of nucleotide and drug metabolism. Pharmacol Ther. 2005;107:1–30.PubMedCrossRefGoogle Scholar
  182. 182.
    Thiel M, Caldwell CC, Sitkovsky MV. The critical role of adenosine A2A receptors in downregulation of inflammation and immunity in the pathogenesis of infectious diseases. Microbes Infect. 2003;5:515–26.PubMedCrossRefGoogle Scholar
  183. 183.
    Milne GR, Palmer TM. Anti-inflammatory and immunosuppressive effects of the A2A adenosine receptor. Sci World J. 2011;11:320–39.CrossRefGoogle Scholar
  184. 184.
    Kinsey GR, et al. Autocrine adenosine signaling promotes regulatory T cell–mediated renal protection. J Am Soc Nephrol. 2012;23:1528–37.PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Ohta A, et al. The development and immunosuppressive functions of CD4(+) CD25(+) FoxP3(+) regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front Immunol. 2012;3:190.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Allard B, Beavis PA, Darcy PK, Stagg J. Immunosuppressive activities of adenosine in cancer. Curr Opin Pharmacol. 2016;29:7–16.PubMedCrossRefGoogle Scholar
  187. 187.
    Pulte D, et al. CD39 expression on T lymphocytes correlates with severity of disease in patients with chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk. 2011;11:367–72.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Stagg J, Smyth MJ. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene. 2010;29:5346–58.PubMedCrossRefGoogle Scholar
  189. 189.
    Young A, Mittal D, Stagg J, Smyth MJ. Targeting cancer-derived adenosine: new therapeutic approaches. Cancer Discov. 2014;4:879–88.PubMedCrossRefGoogle Scholar
  190. 190.
    Hay CM, et al. Targeting CD73 in the tumor microenvironment with MEDI9447. Oncoimmunology. 2016;5:e1208875.PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    De Simone M, et al. Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells. Immunity. 2016;45:1135–47.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • C. Maherzi
    • 1
    • 2
  • F. Onodi
    • 1
  • E. Tartour
    • 1
    • 2
    • 3
  • M. Terme
    • 1
    • 2
  • C. Tanchot
    • 1
    • 2
    Email author
  1. 1.INSERM U970, PARCC (Paris-Cardiovascular Research Center)ParisFrance
  2. 2.Faculté de MédecineUniversité Paris Descartes, Sorbonne Paris CitéParisFrance
  3. 3.Service d’immunologie biologique, Hôpital Européen Georges Pompidou, AP-HPParisFrance

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