Inhibition of CD39 enzymatic function at the surface of tumor cells alleviates their immunosuppressive activity.
The ectonucleotidases CD39 and CD73 hydrolyze extracellular adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to generate adenosine, which binds to adenosine receptors and inhibits T-cell and natural killer (NK)-cell responses, thereby suppressing the immune system. The generation of adenosine via the CD39/CD73 pathway is recognized as a major mechanism of regulatory T cell (Treg) immunosuppressive function. The number of CD39⁺ Tregs is increased in some human cancers, and the importance of CD39⁺ Tregs in promoting tumor growth and metastasis has been demonstrated using several in vivo models. Here, we addressed whether CD39 is expressed by tumor cells and whether CD39⁺ tumor cells mediate immunosuppression via the adenosine pathway. Immunohistochemical staining of normal and tumor tissues revealed that CD39 expression is significantly higher in several types of human cancer than in normal tissues. In cancer specimens, CD39 is expressed by infiltrating lymphocytes, the tumor stroma, and tumor cells. Furthermore, the expression of CD39 at the cell surface of tumor cells was directly demonstrated via flow cytometry of human cancer cell lines. CD39 in cancer cells displays ATPase activity and, together with CD73, generates adenosine. CD39⁺CD73⁺ cancer cells inhibited the proliferation of CD4 and CD8 T cells and the generation of cytotoxic effector CD8 T cells (CTL) in a CD39- and adenosine-dependent manner. Treatment with a CD39 inhibitor or blocking antibody alleviated the tumor-induced inhibition of CD4 and CD8 T-cell proliferation and increased CTL- and NK cell-mediated cytotoxicity. In conclusion, interfering with the CD39-adenosine pathway may represent a novel immunotherapeutic strategy for inhibiting tumor cell-mediated immunosuppression.
OREGA Biotech, Ecully, France. jeremy.bastid@orega-biotech.com jean-francois.eliaou@inserm.fr armand.bensussan@inserm.fr.
Jeremy
J
Bastid
OREGA Biotech, Ecully, France.
Anne
A
Regairaz
IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U896; Université Montpellier 1; CRLC Val d'Aurelle Paul Lamarque, Montpellier, France.
Nathalie
N
Bonnefoy
OREGA Biotech, Ecully, France. IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U896; Université Montpellier 1; CRLC Val d'Aurelle Paul Lamarque, Montpellier, France.
Cécile
C
Déjou
Institut Jean Godinot, Reims, France. Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, Reims Cedex, France.
Jérôme
J
Giustiniani
OREGA Biotech, Ecully, France.
Caroline
C
Laheurte
OREGA Biotech, Ecully, France.
Stéphanie
S
Cochaud
IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U896; Université Montpellier 1; CRLC Val d'Aurelle Paul Lamarque, Montpellier, France.
Emilie
E
Laprevotte
Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 976; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Immunologie Dermatologie & Oncologie, Paris, France.
Elisa
E
Funck-Brentano
Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 976; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Immunologie Dermatologie & Oncologie, Paris, France.
Patrice
P
Hemon
IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U896; Université Montpellier 1; CRLC Val d'Aurelle Paul Lamarque, Montpellier, France.
Laurent
L
Gros
IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U896; Université Montpellier 1; CRLC Val d'Aurelle Paul Lamarque, Montpellier, France.
Nicole
N
Bec
IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U896; Université Montpellier 1; CRLC Val d'Aurelle Paul Lamarque, Montpellier, France.
Christian
C
Larroque
OREGA Biotech, Ecully, France.
Gilles
G
Alberici
Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-S 976; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Immunologie Dermatologie & Oncologie, Paris, France. jeremy.bastid@orega-biotech.com jean-francois.eliaou@inserm.fr armand.bensussan@inserm.fr.
Armand
A
Bensussan
IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U896; Université Montpellier 1; CRLC Val d'Aurelle Paul Lamarque, Montpellier, France. Département d'Immunologie, Centre Hospitalier Régional Universitaire de Montpellier et Faculté de Médecine Université Montpellier 1, Montpellier, France. jeremy.bastid@orega-biotech.com jean-francois.eliaou@inserm.fr armand.bensussan@inserm.fr.
Jean-François
JF
Eliaou
D015720:5'-Nucleotidase / Q000276:immunology; D000241:Adenosine / Q000276:immunology*; D000251:Adenosine Triphosphatases / Q000276:immunology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D015703:Antigens, CD / Q000276:immunology; D001081:Apyrase / Q000037:antagonists & inhibitors* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D006801:Humans; D007108:Immune Tolerance; D007694:Killer Cells, Natural / Q000276:immunology; D018047:Receptors, Purinergic P1 / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D015703:Antigens, CD; D018047:Receptors, Purinergic P1; D000255:Adenosine Triphosphate; D015720:5'-Nucleotidase; D000251:Adenosine Triphosphatases; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine