CD73 is overexpressed in many types of human and mouse cancers and is implicated in the control of tumor progression. However, the specific contribution from tumor or host CD73 expression to tumor growth remains unknown to date. Here, we show that host CD73 promotes tumor growth in a T cell–dependent manner and that the optimal antitumor effect of CD73 blockade requires inhibiting both tumor and host CD73. Notably, enzymatic activity of CD73 on nonhematopoietic cells limited tumor-infiltrating T cells by controlling antitumor T cell homing to tumors in multiple mouse tumor models. In contrast, CD73 on hematopoietic cells (including CD4+CD25+ Tregs) inhibited systemic antitumor T cell expansion and effector functions. Thus, CD73 on hematopoietic and nonhematopoietic cells has distinct adenosinergic effects in regulating systemic and local antitumor T cell responses. Importantly, pharmacological blockade of CD73 using its selective inhibitor or an anti-CD73 mAb inhibited tumor growth and completely restored efficacy of adoptive T cell therapy in mice. These findings suggest that both tumor and host CD73 cooperatively protect tumors from incoming antitumor T cells and show the potential of targeting CD73 as a cancer immunotherapy strategy.
Long Wang, Jie Fan, Linda F. Thompson, Yi Zhang, Tahiro Shin, Tyler J. Curiel, Bin Zhang
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Ecto-5′-Nucleotidase (CD73) Deficiency in Mycobacterium tuberculosis-Infected Mice Enhances Neutrophil Recruitment
L Petit-Jentreau, G Jouvion, P Charles, L Majlessi, B Gicquel, L Tailleux, S Ehrt |
Infection and immunity | 2015 |
CD73-mediated adenosine production promotes stem cell-like properties in mouse Tc17 cells
F Flores-Santibáñez, D Fernández, D Meza, G Tejón, L Vargas, L Varela-Nallar, S Arredondo, V Guixé, M Rosemblatt, MR Bono, D Sauma |
Immunology | 2015 |
Advances in Cancer Research
JD Peske, AB Woods, VH Engelhard |
Advances in cancer research | 2015 |
A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy
RD Leone, YC Lo, JD Powell |
Computational and Structural Biotechnology Journal | 2015 |
A2B adenosine receptor activation switches differentiation of bone marrow cells to a CD11c + Gr-1 + dendritic cell subset that promotes the Th17 response: Role of adenosine receptor in DC differentiation
D Liang, A Zuo, H Shao, M Chen, HJ Kaplan, D Sun |
Immunity, Inflammation and Disease | 2015 |
Targeting Ornithine Decarboxylase by -Difluoromethylornithine Inhibits Tumor Growth by Impairing Myeloid-Derived Suppressor Cells
C Ye, Z Geng, D Dominguez, S Chen, J Fan, L Qin, A Long, Y Zhang, TM Kuzel, B Zhang |
Journal of immunology (Baltimore, Md. : 1950) | 2015 |
A non-canonical adenosinergic pathway led by CD38 in human melanoma cells induces suppression of T cell proliferation
F Morandi, B Morandi, AL Horenstein, A Chillemi, V Quarona, G Zaccarello, P Carrega, G Ferlazzo, MC Mingari, L Moretta, V Pistoia, F Malavasi |
Oncotarget | 2015 |
Alternative splicing of human NT5E in cirrhosis and hepatocellular carcinoma produces a negative regulator of ecto-5'-nucleotidase (CD73)
NT Snider, PJ Altshuler, S Wan, TH Welling, J Cavalcoli, MB Omary |
Molecular biology of the cell | 2014 |
Requirement of NK cells for selective A 2A receptor blockade to suppress CD73 + tumor metastasis
L Qin, LF Thompson, TM Kuzel, B Zhang |
Immunotherapy | 2014 |
Human CD4 + CD39 + regulatory T cells produce adenosine upon co-expression of surface CD73 or contact with CD73 + exosomes or CD73 + cells: CD73 co-expression in human CD39 + T reg
PJ Schuler, Z Saze, CS Hong, L Muller, DG Gillespie, D Cheng, M Harasymczuk, M Mandapathil, S Lang, EK Jackson, TL Whiteside |
Clinical & Experimental Immunology | 2014 |
Roles of the Adenosine Receptor and CD73 in the Regulatory Effect of γδ T Cells
Dongchun Liang, Aijun Zuo, Hui Shao, Mingjiazi Chen, Henry J. Kaplan, Deming Sun |
PloS one | 2014 |
Growth and metastasis of B16-F10 melanoma cells is not critically dependent on host CD73 expression in mice
S Burghoff, X Gong, C Viethen, C Jacoby, U Flögel, S Bongardt, A Schorr, A Hippe, B Homey, J Schrader |
BMC Cancer | 2014 |
CD73-Generated Adenosine Is Critical for Immune Regulation during Toxoplasma gondii Infection
DA Mahamed, LE Toussaint, MS Bynoe, JA Appleton |
Infection and immunity | 2014 |
Adenosine A2A Receptors Intrinsically Regulate CD8+ T Cells in the Tumor Microenvironment
C Cekic, J Linden |
Cancer research | 2014 |
Extracellular adenosine metabolism in immune cells in melanoma.
Umansky V, Shevchenko I, Bazhin AV, Utikal J |
Cancer Immunology, Immunotherapy | 2014 |
Expression and clinical significance of CD73 and hypoxia-inducible factor-1α in gastric carcinoma
XX Lu, YT Chen, B Feng, XB Mao, B Yu, XY Chu |
World journal of gastroenterology : WJG | 2013 |
Graft-versus-Host Disease Is Enhanced by Selective CD73 Blockade in Mice
L Wang, J Fan, S Chen, Y Zhang, TJ Curiel, B Zhang, T Eckle |
PloS one | 2013 |
Immunotherapeutic approaches in triple-negative breast cancer: latest research and clinical prospects
J Stagg, B Allard |
Therapeutic advances in medical oncology | 2013 |
Immunity, inflammation and cancer: a leading role for adenosine
L Antonioli, C Blandizzi, P Pacher, G Haskó |
Nature Reviews Cancer | 2013 |
Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy
C Devaud, LB John, JA Westwood, PK Darcy, MH Kershaw |
OncoImmunology | 2013 |
Peripheral tissue homing receptor control of naïve, effector, and memory CD8 T cell localization in lymphoid and non-lymphoid tissues
CC Brinkman, JD Peske, VH Engelhard |
Frontiers in immunology | 2013 |
Overexpression of CD73 in Prostate Cancer is Associated with Lymph Node Metastasis
Q Yang, J Du, L Zu |
Pathology & Oncology Research | 2013 |
Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors
PA Beavis, U Divisekera, C Paget, MT Chow, LB John, C Devaud, K Dwyer, J Stagg, MJ Smyth, PK Darcy |
Proceedings of the National Academy of Sciences | 2013 |
CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer
S Loi, S Pommey, B Haibe-Kains, PA Beavis, PK Darcy, MJ Smyth, J Stagg |
Proceedings of the National Academy of Sciences | 2013 |
CD73 and adenosine generation in the creation of regulatory microenvironments
FS Regateiro, SP Cobbold, H Waldmann |
Clinical & Experimental Immunology | 2013 |
A delicate balance
LF Thompson, H Tsukamoto, P Chernogorova, R Zeiser |
OncoImmunology | 2013 |
Ectonucleotidases in solid organ and allogeneic hematopoietic cell transplantation
P Chernogorova, R Zeiser |
Journal of Biomedicine and Biotechnology | 2012 |
Production of adenosine by ectonucleotidases: a key factor in tumor immunoescape
F Ghiringhelli, M Bruchard, F Chalmin, C Rébé |
Journal of Biomedicine and Biotechnology | 2012 |
CD73-generated adenosine: orchestrating the tumor-stroma interplay to promote cancer growth
B Allard, M Turcotte, J Stagg |
Journal of Biomedicine and Biotechnology | 2012 |
Ectonucleotidases in tumor cells and tumor-associated immune cells: an overview
LS Bergamin, E Braganhol, RF Zanin, MI Edelweiss, AM Battastini |
Journal of Biomedicine and Biotechnology | 2012 |
CD73 promotes tumor growth and metastasis
B Zhang |
OncoImmunology | 2012 |
Host CD73 impairs anti-tumor immunity
M Salmi, S Jalkanen |
OncoImmunology | 2012 |
The double-edge sword effect of anti-CD73 cancer therapy
J Stagg |
OncoImmunology | 2012 |
NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity
H Wang, S Lee, CL Nigro, L Lattanzio, M Merlano, M Monteverde, R Matin, K Purdie, N Mladkova, D Bergamaschi, C Harwood, N Syed, P Szlosarek, E Briasoulis, A McHugh, A Thompson, A Evans, I Leigh, C Fleming, GJ Inman, E Hatzimichael, C Proby, T Crook |
British Journal of Cancer | 2012 |
Immunomodulation via Chemotherapy and Targeted Therapy: A New Paradigm in Breast Cancer Therapy?
J Stagg, F Andre, S Loi |
Breast Care | 2012 |
Inhibition of CD73 improves B cell-mediated anti-tumor immunity in a mouse model of melanoma
G Forte, R Sorrentino, A Montinaro, A Luciano, IM Adcock, P Maiolino, C Arra, C Cicala, A Pinto, S Morello |
Journal of immunology (Baltimore, Md. : 1950) | 2012 |
Deficiency of CD73/ecto-5′-nucleotidase in mice enhances acute graft-versus-host disease
H Tsukamoto, P Chernogorova, K Ayata, UV Gerlach, A Rughani, JW Ritchey, J Ganesan, M Follo, R Zeiser, LF Thompson, M Idzko |
Blood | 2012 |
Tumor microenvironment and lymphocyte infiltration
G Rahir, M Moser |
Cancer Immunology Immunotherapy | 2012 |
CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death
S Serra, AL Horenstein, T Vaisitti, D Brusa, D Rossi, L Laurenti, G D'Arena, M Coscia, C Tripodo, G Inghirami, SC Robson, G Gaidano, F Malavasi, S Deaglio |
Blood | 2011 |
Role of CD73 and extracellular adenosine in disease
SC Robson |
Purinergic Signalling | 2011 |
Intrinsic Growth Deficiencies of Mesenchymal Stromal Cells in Myelodysplastic Syndromes
CM Aanei, P Flandrin, FZ Eloae, E Carasevici, D Guyotat, E Wattel, L Campos |
Stem Cells and Development | 2011 |
Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd |
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology | 2009 |