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Cancer Immunol Res. 2015 Mar;3(3):254-65. doi: 10.1158/2326-6066.CIR-14-0018. Epub 2014 Nov 17.

Inhibition of CD39 enzymatic function at the surface of tumor cells alleviates their immunosuppressive activity.

Author information

1
OREGA Biotech, Ecully, France. jeremy.bastid@orega-biotech.com jean-francois.eliaou@inserm.fr armand.bensussan@inserm.fr.
2
OREGA Biotech, Ecully, France.
3
IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM, U896; Université Montpellier 1; CRLC Val d'Aurelle Paul Lamarque, Montpellier, France.
4
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.
5
Institut Jean Godinot, Reims, France. Université Reims-Champagne-Ardenne, DERM-I-C, EA7319, Reims Cedex, France.
6
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.
7
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.
8
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.

Abstract

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.

PMID:
25403716
DOI:
10.1158/2326-6066.CIR-14-0018
[Indexed for MEDLINE]
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