CD73 in Autoimmune Arthritis

Adenosine is a potent anti-inflammatory molecule that plays an important role in many diseases. Extracellular levels of adenosine are determined by a combination of membrane transporters and ecto-nucleotidases such as CD73. Therapeutic targeting of the adenosinergic pathway, such as administration of adenosine receptor agonists, could be a valuable approach in the treatment of rheumatoid arthritis(RA). Until recently, the role of CD73 in RA pathogenesis had not been established. Using CD73-deficient gene-targeted mice, we demonstrated that CD73 plays a critical protective role in collagen-induced arthritis (CIA) in mice. Our findings, together with the results of recently published human studies, thus suggests that enhancement of CD73 activity may be a novel therapeutic approach in RA

Adenosine A2a receptor promotes lymphangiogenesis and lymph node metastasis

The formation of new lymphatic vessels, or lymphangiogenesis, is a critical step of the tissue repair program. In pathological conditions involving chronic inflammation or tumorigenesis, this process is often dysregulated and can contribute to disease progression. Yet, lymphangiogenesis is still incompletely understood. In this study, we identified A2a adenosinergic signaling as an important regulator of inflammatory and tumor-associated lymphangiogenesis. Using Adora2a (A2a)-deficient mice, we demonstrated that A2a signaling was involved in the formation of new lymphatic vessels in the context of peritoneal inflammation. We also demonstrated that tumor-associated and sentinel lymph node lymphangiogenesis were impaired in A2a-deficient mice, protecting them from lymph node metastasis. Notably, A2a signaling in both hematopoietic and non-hematopoietic cells contributed to sentinel lymph node metastasis. In A2a-deficient tumor-draining lymph nodes, impaired lymphangiogenesis was associated with a reduced accumulation of B cells and decreased VEGF-C levels. Supporting a role for non-hematopoietic A2a signaling, we observed that primary murine lymphatic endothelial cells (LEC) predominantly expressed A2a receptor and that A2a signaling blockade altered LEC capillary tube formation in vitro. Finally, we observed that Adora2a, Nt5e and Entpd1 gene expression positively correlated with Lyve1, Pdpn and Vegfc in several human cancers, thereby supporting the notion that adenosine production and A2a receptor activation might promote lymphangiogenesis in human tumors. In conclusion, our study highlights a novel pathway regulating lymphangiogenesis and further supports the use of A2a or adenosine blocking agents to inhibit pathological lymphangiogenesis in cancers and block the dissemination of tumor cells through the lymphatic system.SCOPUS: ar.jDecretOANoAutActifinfo:eu-repo/semantics/publishe

CD73-A2a adenosine receptor axis promotes innate B cell antibody responses to pneumococcal polysaccharide vaccination

<div><p>Many individuals at risk of streptococcal infection respond poorly to the pneumococcal polysaccharide vaccine Pneumovax 23. Identification of actionable pathways able to enhance Pneumovax responsiveness is highly relevant. We investigated the contribution of the extracellular adenosine pathway regulated by the ecto-nucleotidase CD73 in Pneumovax-induced antibody responses. Using gene-targeted mice, we demonstrated that CD73-or A2a adenosine receptor deficiency significantly delayed isotype switching. Nevertheless, CD73- or A2aR- deficient adult mice ultimately produced antigen-specific IgG3 and controlled <i>Streptococcus pneumoniae</i> infection as efficiently as wild type (WT) mice. Compared to adults, young WT mice failed to control <i>S</i>. <i>pneumoniae</i> infection after vaccination and this was associated with lower levels of CD73 on innate B cells. We hypothesized that pharmacological activation of A2a receptor may improve Pneumovax 23 immunization in young WT mice. Remarkably, administration of the A2a adenosine receptor agonist CGS 21680 significantly increased IgG3 responses and significantly enhanced survival after <i>S</i>. <i>pneumoniae</i> challenge. Our study thus suggests that pharmacological activation of the A2a adenosine receptor could improve the efficacy of Pneumovax 23 vaccination in individuals at risk of streptococcal infection.</p></div

PolyI:C and CpG Synergize with Anti-ErbB2 mAb for Treatment of Breast Tumors Resistant to Immune Checkpoint Inhibitors.

Innate and adaptive immune cells play an important role in the therapeutic activity of anti-ErbB2 mAbs, such as trastuzumab. In the clinic, breast tumors poorly infiltrated with immune cells are more resistant to trastuzumab, and patients have a worse prognosis. Because type I and II IFNs are critical to the immune-mediated activity of anti-ErbB2 mAb, we investigated the effect of combining polyI:C and CpG with trastuzumab-like therapy in immunocompetent mouse models of ErbB2(+) breast cancer. We demonstrated that in situ delivery of polyI:C and CpG combined to systemic anti-ErbB2 mAb triggered a potent inflammatory response in breast tumors able to induce long-lasting CD8(+) T cell-dependent antitumor immunity. Remarkably, polyI:C and CpG was superior to combined PD-1/CTLA-4 blockade in sensitizing tumors to anti-ErbB2 mAb therapy. Local injection of CpG and polyI:C in a primary tumor significantly enhanced the activity of systemic anti-ErbB2 mAb against a distant untreated tumor. Type I and II IFNs, as well as natural killer cells and CD8(+) T cells, were indispensible to the synergistic activity of the combination treatment. Because synthetic RNA analogues and CpG oligodeoxynucleotides have been safely used in clinical trials, our study supports combination treatments with anti-ErbB2 mAbs. Cancer Res; 77(2); 312-9. ©2016 AACR.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

A2a receptor agonist enhances Pneumovax 23 responses in young mice.

<p>Young (3-week-old) WT mice were immunized i.p. with 10 μg of Pneumovax 23 and were subsequently treated daily with CGS 21680 or vehicle only DMSO (control) for 4 weeks as described in methods. Sera were analyzed by ELISA for anti-PPS3 specific Abs at day 0, 7, 14 and 28 after vaccination. On day 28, mice were challenged by i.p. injection of <i>S</i>. <i>pneumoniae</i> (5x10³ CFU). (A) Anti-PPS3 IgM and IgG3 OD (450–570) readings are shown (means ± standard errors are shown; *: p<0.05; **: p<0.01 by Student’s T test). (B) IgG3 mean reciprocal titers at day 7, 24 and 28 showing individual mice (means ± standard errors are shown; *: p<0.05; by One-way ANOVA). (C) Survival of infected mice (*: p≤0.05 by log-rank test; n.s.: p>0.05; survival was compared to non-vaccinated mice unless indicated by a bracket).</p

CD73-deficiency is associated with delayed IgG3 response after Pneumovax 23 vaccination.

<p>8 to 12-week-old WT and CD73 KO mice were immunized i.p. with Pneumovax 23 and sera were analyzed by ELISA for anti-PPS3 specific Abs at day 0, 7 and 28 after vaccination. On day 28, mice were challenged by i.p. injection of <i>S</i>. <i>pneumoniae</i> (10⁵ CFU). (A) Anti-PPS3 IgM and IgG3 OD (450–570) readings are shown (means ± standard errors are shown; *: p<0.05; **: p<0.01 by Student’s T test). (B) Combined results from 2 experiments pooling 20 WT and 19 CD73 KO mice showing IgM and IgG3 mean reciprocal titers at day 7 and 28 (means ± standard errors are shown; **: p<0.01; by One-way ANOVA; brackets are shown when significantly different from day 7 and 28 for a given group). (C) Survival of infected mice was monitored (*: p<0.05 by log-rank test; survival was compared to non-vaccinated mice, unless indicated by brackets; n.s: not significant).</p

CD73 KO mice have similar numbers of major B cell subsets.

<p>CD73 KO mice have similar numbers of major B cell subsets.</p

Preserved steady-state functions of B-1 B cells in CD73-deficient mice.

<p>(A) Total serum IgM levels were measured in adult WT and CD73 KO mice (8 to 12-week-old). Titration curves of one experiment are shown (means ± standard errors; *: p<0.05 by Student’s T test). Bar graphs were generated from three independent experiments (mean reciprocal titers ± standard errors are shown; n.s.: not significant; by Student T test). (B) Serum anti-phosphorylcholine (PC) IgM levels were measured in adult WT and CD73 KO mice (8 to 12-week-old). Titration curves of one experiment are shown. Bar graph were generated from three independent experiments (mean reciprocal titers ± standard errors are shown; n.s: not significant; by Student T test). (C) Naïve adult WT and CD73 KO mice (8 to 12-week-old) were injected i.p. with 10 CFU of <i>S</i>. <i>pneumoniae</i> and survival monitored over time (n.s: p>0.05 by log-rank test).</p