Dataset Information

Targeting CD73 in the tumor microenvironment with MEDI9447.

ABSTRACT: MEDI9447 is a human monoclonal antibody that is specific for the ectoenzyme CD73 and currently undergoing Phase I clinical trials. Here we show that MEDI9447 is a potent inhibitor of CD73 ectonucleotidase activity, with wide ranging immune regulatory consequences. MEDI9447 results in relief from adenosine monophosphate (AMP)-mediated lymphocyte suppression in vitro and inhibition of mouse syngeneic tumor growth in vivo. In contrast with other cancer immunotherapy agents such as checkpoint inhibitors or T-cell agonists, MEDI9447 drives changes in both myeloid and lymphoid infiltrating leukocyte populations within the tumor microenvironment of mouse models. Changes include significant alterations in a number of tumor micro-environmental subpopulations including increases in CD8(+) effector cells and activated macrophages. Furthermore, these changes correlate directly with responder and non-responder subpopulations within animal studies using syngeneic tumors. Combination data showing additive activity between MEDI9447 and anti-PD-1 antibodies using human cells in vitro and mouse tumor models further demonstrate the potential value of relieving adenosine-mediated immunosuppression. Based on these data, a Phase I study to test the safety, tolerability, and clinical activity of MEDI9447 in cancer patients was initiated (NCT02503774).

SUBMITTER: Hay CM

PROVIDER: S-EPMC5007986 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Targeting CD73 in the tumor microenvironment with MEDI9447.

Hay Carl M CM Sult Erin E Huang Qihui Q Mulgrew Kathy K Fuhrmann Stacy R SR McGlinchey Kelly A KA Hammond Scott A SA Rothstein Raymond R Rios-Doria Jonathan J Poon Edmund E Holoweckyj Nick N Durham Nicholas M NM Leow Ching Ching CC Diedrich Gundo G Damschroder Melissa M Herbst Ronald R Hollingsworth Robert E RE Sachsenmeier Kris F KF

Oncoimmunology 20160711 8

MEDI9447 is a human monoclonal antibody that is specific for the ectoenzyme CD73 and currently undergoing Phase I clinical trials. Here we show that MEDI9447 is a potent inhibitor of CD73 ectonucleotidase activity, with wide ranging immune regulatory consequences. MEDI9447 results in relief from adenosine monophosphate (AMP)-mediated lymphocyte suppression in vitro and inhibition of mouse syngeneic tumor growth in vivo. In contrast with other cancer immunotherapy agents such as checkpoint inhibi ...[more]

PMID: 27622077

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Project description:Background: The role of senescent cells in the tumor microenvironment (TME) is usually bilateral, and diverse therapeutic approaches, such as radiotherapy and chemotherapy, can induce cellular senescence. Cellular interactions are widespread in the TME, and tumor cells reprogram immune cells metabolically by producing metabolites. However, how senescent cells remodel the metabolism of TME remains unclear. This study aimed to explore precise targets to enhance senescent cells-induced anti-tumor immunity from a metabolic perspective. Methods: The in vivo senescence model was induced by 8 Gy×3 radiotherapy or cisplatin chemotherapy, and the in vitro model was induced by 10 Gy-irradiation or cisplatin treatment. Metabonomic analysis and ELISA assay on tumor interstitial fluid were performed for metabolites screening. Marker expression and immune cell infiltration in the TME were analyzed by flow cytometry. Cell co-culture system and senescence-conditioned medium were used for crosstalk validation in vitro. RNA sequencing and rescue experiments were conducted for mechanism excavation. Immunofluorescence staining and single-cell transcriptome profiling analysis were performed for clinical validation. Results: We innovatively reveal the metabolic landscape of the senescent TME, characterized with the elevation of adenosine. It is attributed to the senescent tumor cell-induced CD73 upregulation of tumor-associated macrophages (TAMs). CD73 expression in TAMs is evoked by SASP-related pro-inflammatory cytokines, especially IL-6, and regulated by JAK/STAT3 pathway. Consistently, a positive correlation between tumor cells senescence and TAMs CD73 expression is identified in lung cancer clinical specimens and databases. Lastly, blocking CD73 in a senescent background suppresses tumors and activates CD8+ T cell-mediated antitumor immunity. Conclusions: TAMs expressed CD73 contributes significantly to the adenosine accumulation in the senescent TME, suggesting targeting CD73 is a novel synergistic anti-tumor strategy in the aging microenvironment.

Project description:BackgroundCD73 is adenosine generation molecule, which is involved in the immune regulation. However, the roles of CD73 in the tumor microenvironment remain unknown.MethodsCD73 expression levels in pan-cancers were analyzed, based on The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and Human Protein ALTAS (HPA) databases. Kaplan-Meier (KM) plotter was used to analyze the prognostic values of CD73. Immune scores in pan-cancers was evaluated by ESTIMATE. TIMER2.0 and UCSCXena were used to explore the correlation between CD73 and immune infiltration/immune checkpoints/tumor mutation burden (TMB)/microsatellite instability (MSI). CD73 expression correlated genes in tumor tissues were screened by using LinkedOmics tool.ResultsFirstly, CD73 was significant increased in following cancer types: esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), brain lower grade glioma (LGG), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD) and stomach adenocarcinoma (STAD). Secondly, high CD73 expression was associated with poor overall survival in patients with breast invasive carcinoma (BRCA), CESC, HNSC, liver hepatocellular carcinoma (LIHC), LUAD, lung squamous cell carcinoma (LUSC), PAAD and STAD. However, in KIRC and UCEC, patients high CD73 expression showed a favorable prognosis. Thirdly, the immune scores of the high CD73 expression in bladder urothelial carcinoma (BLCA), BRCA, kidney chromophobe (KICH), LUAD, LUSC, ovarian serous cystadenocarcinoma (OV), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), and skin cutaneous melanoma (SKCM) were significant higher than that of patients with low CD73 expression. Furthermore, we observed a positive correlation between CD73 and the multiple immune cells infiltration, including CD4+ memory T cells, CD8+ T cells, Treg cells, myeloid DC and macrophage, particularly in BRCA and LUAD. There was no strong correlation between CD73 and TMB/MSI. In LUAD, CD73 expression correlated genes were mainly enrichment in positive regulation of cell proliferation, cell adhesion, positive regulation of kinase activity, cellular response to LPS. However, in UCEC, CD73 correlated genes were mainly associated with fatty acid omega-oxidation, protein localization to endoplasmic reticulum exit site, endoplasmic reticulum to Golgi vesicle-mediated transport.ConclusionCD73 could be used to predict the prognosis of patients with several cancers. The potential functional mechanism of CD73 involved in cancer progress may not only dependent on its immunomodulatory effects.

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Targeting CD73 in the tumor microenvironment with MEDI9447.

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Targeting CD73 in the tumor microenvironment with MEDI9447.

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