Blocking Antibodies Targeting the CD39/CD73 Immunosuppressive Pathway Unleash Immune Responses in Combination Cancer Therapies

Perrot, Ivan; Michaud, Henri; Giraudon-Paoli, Marc; Augier, Séverine; Docquier, Aurélie; Gros, Laurent; Courtois, Rachel; Déjou, Cécile; Jecko, Diana; Becquart, O.; Rispaud-Blanc, Hélène; Gauthier, Laurent; Rossi, Benjamín; Chanteux, Stéphanie; Gourdin, Nicolas; Amigues, Béatrice; Roussel, Alain; Bensussan, Armand; Eliaou, Jean‐François; Bastid, Jérémy; Romagné, François; Morel, Yannis; Narni-Mancinelli, Émilie; Vivier, Éric; Paturel, Carine; Bonnefoy, Nathalie

doi:10.1016/j.celrep.2019.04.091

Cited by 323 publications

(301 citation statements)

References 49 publications

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“…CD39 and CD73 can participate in an immunosuppressive pathway that leads to the degradation of the (immunostimulatory) pool of extracellular ATP to the immunosuppressive metabolite adenosine. Indeed, pharmacological inhibitors targeting CD39, CD73, or adenosinergic receptors are being developed for immunostimulation, exemplifying yet another strategy for the metabolic intervention on cancer. However, it is also known that some facets of immunosurveillance (and in particular T cell expansion) may rely on OXPHOS .…”

Section: Conclusion Limitations and Perspectivesmentioning

confidence: 99%

Oxidative phosphorylation as a potential therapeutic target for cancer therapy

Sica

Pedro

Stoll

et al. 2019

Intl Journal of Cancer

152

114

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In contrast to prior belief, cancer cells require oxidative phosphorylation (OXPHOS) to strive, and exacerbated OXPHOS dependency frequently characterizes cancer stem cells, as well as primary or acquired resistance against chemotherapy or tyrosine kinase inhibitors. A growing arsenal of therapeutic agents is being designed to suppress the transfer of mitochondria from stromal to malignant cells, to interfere with mitochondrial biogenesis, to directly inhibit respiratory chain complexes, or to disrupt mitochondrial function in other ways. For the experimental treatment of cancers, OXPHOS inhibitors can be advantageously combined with tyrosine kinase inhibitors, as well as with other strategies to inhibit glycolysis, thereby causing a lethal energy crisis. Unfortunately, most of the preclinical data arguing in favor of OXPHOS inhibition have been obtained in xenograft models, in which human cancer cells are implanted in immunodeficient mice. Future studies on OXPHOS inhibitors should elaborate optimal treatment schedules and combination regimens that stimulate—or at least are compatible with—anticancer immune responses for long‐term tumor control.

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Section: Conclusion Limitations and Perspectivesmentioning

confidence: 99%

Oxidative phosphorylation as a potential therapeutic target for cancer therapy

Sica

Pedro

Stoll

et al. 2019

Intl Journal of Cancer

152

114

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“…In the hypoxic TME, NAD+ is produced by the salvage pathway and is metabolized by ectoenzymes to form adenosine, a nucleoside that regulates the immune response. In hypoxic conditions, adenosine suppresses the anti-tumor immune response by recruiting myeloid-derived suppressor cells and T regulatory cells, which inhibits the activity of T effector cells and thus favors tumor progression [18,19]. CD38 is one of the three ectoenzymes involved in the production of adenosine through the CD38/CD203a/CD73 adenosinergic pathway.…”

Section: The Role Of Cd38 In the Tmementioning

confidence: 99%

“…This inhibits both the innate and the adaptive immune response, and results in an immunosuppressive TME. Adenosine further suppresses the anti-tumor immune response under hypoxic conditions by recruiting myeloid-derived suppressor cells and T regulatory cells, further inhibiting the activity of T effector cells and favoring tumor progression [18,19]. Previous studies have shown that immunosuppression in the TME can be reduced by inhibiting either the enzymes or receptors in the adenosinergic pathway.…”

Section: The Role Of Cd38 In the Tmementioning

confidence: 99%

The Roles of CD38 and CD157 in the Solid Tumor Microenvironment and Cancer Immunotherapy

Gan

Lim

et al. 2019

Cells

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The tumor microenvironment (TME) consists of extracellular matrix proteins, immune cells, vascular cells, lymphatics and fibroblasts. Under normal physiological conditions, tissue homeostasis protects against tumor development. However, under pathological conditions, interplay between the tumor and its microenvironment can promote tumor initiation, growth and metastasis. Immune cells within the TME have an important role in the formation, growth and metastasis of tumors, and in the responsiveness of these tumors to immunotherapy. Recent breakthroughs in the field of cancer immunotherapy have further highlighted the potential of targeting TME elements, including these immune cells, to improve the efficacy of cancer prognostics and immunotherapy. CD38 and CD157 are glycoproteins that contribute to the tumorigenic properties of the TME. For example, in the hypoxic TME, the enzymatic functions of CD38 result in an immunosuppressive environment. This leads to increased immune resistance in tumor cells and allows faster growth and proliferation rates. CD157 may also aid the production of an immunosuppressive TME, and confers increased malignancy to tumor cells through the promotion of tumor invasion and metastasis. An improved understanding of CD38 and CD157 in the TME, and how these glycoproteins affect cancer progression, will be useful to develop both cancer prognosis and treatment methods. This review aims to discuss the roles of CD38 and CD157 in the TME and cancer immunotherapy of a range of solid tumor types.Cells 2020, 9, 26 2 of 18 inhibit tumor growth and development [5,9]. Surface glycoproteins expressed by immune infiltrates can be used as biomarkers for classification of the immune cells. These glycoproteins also influence the pro-or anti-tumor activity of immune cells. Thus, the presence and functions of glycoproteins on the surface of tumor immune infiltrates are currently subjected to intense study.CD38 and CD157 are two such glycoproteins of particular interest in the field of immunotherapy. They are coded by contiguous gene sequences found on human chromosome 4, and are thought to originate from gene duplication. These gene sequences share similarities in terms of length and the organization of introns and exons, and the resultant proteins share similar functions [10]. CD38 and CD157 function as both receptors and ectoenzymes, and belong to the same family of nicotinamide adenine dinucleotide (NAD+) converting enzymes.CD38 is involved in lymphocyte activation, proliferation and adhesion. Initially thought to be expressed only by thymic lymphocytes, it has since been found to be ubiquitously expressed by immune cells, including B lymphocytes, natural killer cells and monocytes; and its expression varies across both lymphoid and non-lymphoid tissues [10,11]. In contrast, CD157 is mainly expressed by cells derived from the myeloid lineage, and in particular by neutrophils and monocytes. CD157 is also expressed by a wide range of non-lymphoid tissues, including vascular endothelium, kidney collecting tubu...

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“…In the last few years, exciting progress has been made in the development of immunotherapy for the treatment of cancer patients. Modulation of the immune system through a small‐molecule approach offers several unique advantages (e.g., lower cost and ease of administration) that are complementary to and potentially synergistic with immuno‐oncology approaches using monoclonal antibodies . This is exemplified by the association of two monoclonal antibodies (mAbs), one targeting CD73 (MEDI‐9447) and one neutralizing the immune check point PD‐1.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Substituted 5′‐Aminoadenosine Derivatives and Evaluation of Their Inhibitory Potential toward CD73

et al. 2019

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Derivatives of 5′‐aminoadenosine containing methyl carboxylate, methyl phosphonate, gem‐bisphosphonate, bis(methylphosphonate), and α‐carboxylmethylphosphonate or phosphonoacetate moieties were synthesized from key intermediate 5′‐aminonucleoside. These nucleotide analogues were envisaged as 5′‐mono‐ or diphosphate nucleoside mimics. All compounds were evaluated for CD73 inhibition in a cell‐based assay (MDA‐MB‐231) and toward the purified recombinant protein. Most of them failed to reach significant inhibition of AMP hydrolysis by CD73 at 100 μm. Among the new compounds, the most interesting candidates, 5 (5′‐deoxy‐5′‐N‐phosphonomethyladenosine) and 7 (5′‐deoxy‐5′‐N‐(ethoxyphosphorylacetate)adenosine), inhibited recombinant CD73 by 36 and 46 % and cellular CD73 by 61 and 45 % at 100 μm, respectively. Molecular modeling partially explains this lack of activity, as the initially predicted docking scores had been encouraging, especially for compound 9.

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Blocking Antibodies Targeting the CD39/CD73 Immunosuppressive Pathway Unleash Immune Responses in Combination Cancer Therapies

Cited by 323 publications

References 49 publications

Oxidative phosphorylation as a potential therapeutic target for cancer therapy

Oxidative phosphorylation as a potential therapeutic target for cancer therapy

The Roles of CD38 and CD157 in the Solid Tumor Microenvironment and Cancer Immunotherapy

Synthesis of Substituted 5′‐Aminoadenosine Derivatives and Evaluation of Their Inhibitory Potential toward CD73

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