CD73-adenosine reduces immune responses and survival in ovarian cancer patients

Gaudreau, Pierre-Olivier; Allard, Bertrand; Turcotte, Martin; Stagg, John

doi:10.1080/2162402x.2015.1127496

Cited by 37 publications

(30 citation statements)

References 10 publications

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“…We and others demonstrated that high levels of CD73 in the TME are generally associated with worse prognosis (4)(5)(6)(7)(8). In some cases, CD73 expression abrogates the good prognosis associated with tumor-infiltrating CD8 þ lymphocytes (TIL), consistent with its immunosuppressive function (9).…”

Section: Introductionmentioning

confidence: 72%

CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy

et al. 2017

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Expression of the ectonucleotidase CD73 by tumor cells, stromal cells, and immune cells is associated in cancer with immune suppression. In this study, we investigated the role of CD73 on the activity of the anti-HER2/ErbB2 monoclonal antibody (mAb) trastuzumab. In a prospective, randomized phase III clinical trial evaluating the activity of trastuzumab, high levels of CD73 gene expression were associated significantly with poor clinical outcome. In contrast, high levels of PD-1 and PD-L1 were associated with improved clinical outcome. In immunocompetent mouse models of HER2/ErbB2-driven breast cancer, CD73 expression by tumor cells and host cells significantly suppressed immune-mediated responses mediated by anti-ErbB2 mAb. Furthermore, anti-CD73 mAb therapy enhanced the activity of anti-ErbB2 mAb to treat engrafted or spontaneous tumors as well as lung metastases. Gene ontology enrichment analysis from gene-expression data revealed a positive association of CD73 expression with extracellular matrix organization, TGFβ genes, epithelial-to-mesenchymal transition (EMT) transcription factors and hypoxia-inducible-factor (HIF)-1 gene signature. Human mammary cells treated with TGFβ or undergoing EMT upregulated CD73 cell-surface expression, confirming roles for these pathways. In conclusion, our findings establish CD73 in mediating resistance to trastuzumab and provide new insights into how CD73 is regulated in breast cancer. .

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Section: Introductionmentioning

confidence: 72%

CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy

et al. 2017

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“…The enzymatic functions refer to CD73-generated adenosine playing an important role in tumor immune tolerance. Extracellular ADO can exert effect on tumor immune microenvironment through multiple pathways [ 1 , 13 ]: 1) Limiting cytotoxic activity of effective immune cells: ADO significantly reduces CD8+ T cells homing and inhibits NK cells by interfering with the process of granule exocytosis and reducing the ability of NK cells to adhere to tumor cells [ 14 , 15 ]. 2) Enhancing immunosuppressive effects: ADO inhibits M1 macrophage activation and induces M2 macrophage polarization via A2A and A2B receptors [ 16 – 18 ].…”

Section: Introductionmentioning

confidence: 99%

Prognositic value of CD73-adenosinergic pathway in solid tumor: A meta-analysis and systematic review

et al. 2017

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CD73 is a glycosylphosphatidylinositol (GPI) anchored cell surface protein that is encoded by NT5E gene, plays multiple roles in tumor processes. Previous studies have presented a potential value of CD73 served as a detectable biomarker for prognosis of several solid tumors, but the results were more controversially. A comprehensive meta-analysis was conducted to precisely evaluate the prognostic role of CD73 in solid tumors. The included studies were searched in PubMed, Web of Science and EBSCO from Jan 1990 to Jan 2016. Pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) for overall survival (OS), disease free survival (DFS) were carried out using a fixed or random effects model. Totally, 13 studies about 12,533 patients were included. CD73-high expression was correlating with poor OS (pooled HR = 1.28, 95% CI = 1.19–1.37). In addition, CD73 expression had borderline association with worse DFS (pooled HR = 1.28, 95% CI = 1.01–1.62). Egger’s tests indicated that there was no evidence of significant publication bias. CD73 is an efficient prognostic biomarker in solid tumors, and over-expression of CD73 is associated with inverse OS or DFS. But this predictive value and target therapy for clinical practice yet needs advanced research.

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“…We optimized a multiplex immunofluorescence (IF) panel on a test CRLM TMA to concurrently detect CD73, cytokeratins to compartmentalize stromal vs. epithelial expression patterns, and DAPI for nuclear staining of cells. As for other tumor types, [18][19][20][21] the non-patchy expression of CD73 made it suitable for larger scale TMA quantification. We used standard deparaffinization and rehydratation protocols, antigen retrieval (Dako S1699) in sub-boiling conditions for 40 min, and protein-block (Dako X0909) followed by specific staining with primary antibodies against CD73 (Abcam ab91086, 1:300 dilution), and cytokeratins 8/18 (Dako IR094, 1:2 dilution).…”

Section: Immunofluorescencementioning

confidence: 99%

Prognostic value of CD73 expression in resected colorectal cancer liver metastasis

et al. 2020

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Immune checkpoint blockade has not yet been effective in patients with mismatch repair proficient metastatic colorectal cancer. Targeting immunosuppressive metabolic pathways is being explored as a new immunotherapeutic approach. We assessed whether CD73, the rate limiting enzyme that catalyzes the degradation of extracellular AMP into immunosuppressive adenosine, could be an immunological determinant of colorectal liver metastases (CRLMs). By immunofluorescence on tissue microarrays, intratumoral CD73 expression (tCD73) was analyzed in 391 CRLMs resected in 215 patients, and soluble CD73 (sCD73) was measured by ELISA in the pre-operative serum of 193 patients. High tCD73 was associated with worse pathological features, such as multiple and larger CRLMs, and poorer pathologic response to pre-operative chemotherapy. The median time to recurrence and diseasespecific survival after CRLM resection was significantly shorter in patients with high tCD73 (11.0 and 46.4 months, respectively) compared with low tCD73 (19.0 and 61.5 months, respectively). tCD73 was strongly associated with patient outcomes independently of clinicopathological variables. sCD73 did not correlate with tCD73. Patients with high levels of sCD73 also had shorter disease-specific survival. Our results suggested that CD73 in CRLMs may be prognostically informative and may help select patients more likely to respond to adenosine pathway blocking agents.

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CD73-adenosine reduces immune responses and survival in ovarian cancer patients

Cited by 37 publications

References 10 publications

CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy

CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy

Prognositic value of CD73-adenosinergic pathway in solid tumor: A meta-analysis and systematic review

Prognostic value of CD73 expression in resected colorectal cancer liver metastasis

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