The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

Abstract

(2016) The ectoATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSFmacrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27, OncoImmunology, 5:7, e1178025, DOI: 10.1080/2162402X.2016 Targeting mediators that control the generation or the differentiation of immunoregulatory macrophages represents a therapeutic challenge to overcome tumor-associated immunosuppression. The ectonucleotidase CD39 hydrolyzes ATP into extracellular adenosine that exhibits potent immunosuppressive properties when signaling through the A2A adenosine receptor. We report here that CD14 C CD163 C TAM isolated from ovarian cancer patients and macrophages generated in vitro with M-CSF, express high levels of the membrane ectonucleotidase CD39 compared to classically activated macrophages. The CD39 inhibitor POM-1 and adenosine deaminase (ADA) diminished some of the immunosuppressive functions of CD14 high CD163 high CD39 high macrophages, such as IL-10 secretion. We identified the cytokine IL-27, secreted by tumor-infiltrating neutrophils, located close to infiltrating CD163 C macrophages, as a major rheostat of CD39 expression and consequently, on the acquisition of immunoregulatory properties by macrophages. Accordingly, the depletion of IL-27 downregulated CD39 and PD-L1 expression as well as IL-10 secretion by M-CSF-macrophages. Collectively, these data suggest that CD39, drived by IL-27 and CD115 ligands in ovarian cancer, maintains the immunosuppressive phenotype of TAM. This work brings new information on the acquisition of immunosuppressive properties by tumor-infiltrating macrophages.

Consensus guidelines for the definition, detection and interpretation of immunogenic cell death

“…228 IL-10 and TGFB1 are secreted by cancer cells and by immunosuppressive immune cells actively recruited to the TME, such as CD4 + CD25 + FOXP3 + regulatory T (T REG ) cells, M2-polarized tumor-associated macrophages (TAMs), and/or myeloid-derived suppressor cells (MDSCs). [229][230][231] Importantly, these immune cell populations express high levels of ectonucleoside triphosphate Open access diphosphohydrolase 1 (ENTPD1, best known as CD39) and 5'-nucleotidase ecto (NT5E, best known as CD73), [232][233][234] two enzymes that cooperate to convert extracellular ATP into adenosine, which also mediates robust immunosuppressive effects. 235 Thus, T REG cells, M2-polarized TAMs and MDSCs also have direct ICD antagonizing effects.…”

The yin and yang functions of extracellular ATP and adenosine in tumor immunity

“…When compared to CD39 over-expressing mice, colorectal cancer cells and melanoma cells in CD39 deficient models showed significantly slower hepatic and pulmonary metastases [116]. Inhibition of CD39 activity by polyoxometalate1 (POM-1) abrogated production of IL-10 from TAMs, functionally diminished immunosuppressive functions [117]. Even for sarcoma, which lacked effective therapeutic intervention, CD39 inhibitory mAb was proven to have prolonged survival in a lethal metastatic patient-derived sarcoma model [118].…”

The effects of CD14 and IL-27 on induction of endotoxin tolerance in human monocytes and macrophages

“…In addition, IFN-␤ produced in response to LPS is involved in promoting macrophages to the M1 phenotype (86). There are conflicting reports on the role of IFN-␤ in endotoxin tolerance; endotoxin tolerance occurs independent of IFN-␤ production in IFNAR knock-out mice (87), whereas IFN-␤ production has also been attributed to the development of sepsis in murine models, suggesting an association between a refractory state of monocytes and low IFN-␤ production (88). Furthermore, IL-27-treated M2 macrophages exhibit suppressed IL-12/23p40 production (32).…”