CD73 induces GM-CSF/MDSC-mediated suppression of T cells to accelerate pancreatic cancer pathogenesis.

Autor:	King RJ; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Shukla SK; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA., He C; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Vernucci E; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Thakur R; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Attri KS; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Dasgupta A; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Chaika NV; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Mulder SE; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA.; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Abrego J; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Murthy D; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Gunda V; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Pacheco CG; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Grandgenett PM; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Lazenby AJ; Department of Pathology and Microbiology, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Hollingsworth MA; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA.; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 68198, Omaha, NE, USA.; Department of Pathology and Microbiology, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Yu F; Department of Biostatistics, University of Nebraska Medical Center, 68198, Omaha, NE, USA., Mehla K; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA. kamiya.mehla@unmc.edu., Singh PK; The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA. pankaj.singh@unmc.edu.; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 68198, Omaha, NE, USA. pankaj.singh@unmc.edu.; Department of Pathology and Microbiology, University of Nebraska Medical Center, 68198, Omaha, NE, USA. pankaj.singh@unmc.edu.; Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, 68198, Omaha, NE, USA. pankaj.singh@unmc.edu.
Jazyk:	angličtina
Zdroj:	Oncogene [Oncogene] 2022 Feb; Vol. 41 (7), pp. 971-982. Date of Electronic Publication: 2022 Jan 10.
DOI:	10.1038/s41388-021-02132-6
Abstrakt:	Metabolic alterations regulate cancer aggressiveness and immune responses. Given the poor response of pancreatic ductal adenocarcinoma (PDAC) to conventional immunotherapies, we investigated the link between metabolic alterations and immunosuppression. Our metabolic enzyme screen indicated that elevated expression of CD73, an ecto-5'-nucleotidase that generates adenosine, correlates with increased aggressiveness. Correspondingly, we observed increased interstitial adenosine levels in tumors from spontaneous PDAC mouse models. Diminishing CD73 by genetic manipulations ablated in vivo tumor growth, and decreased myeloid-derived suppressor cells (MDSC) in orthotopic mouse models of PDAC. A high-throughput cytokine profiling demonstrated decreased GM-CSF in mice implanted with CD73 knockdowns. Furthermore, we noted increased IFN-γ expression by intratumoral CD4 + and CD8 + T cells in pancreatic tumors with CD73 knockdowns. Depletion of CD4 + T cells, but not CD8 + T cells abrogated the beneficial effects of decreased CD73. We also observed that splenic MDSCs from Nt5e knockdown tumor-bearing mice were incompetent in suppressing T cell activation in the ex vivo assays. Replenishing GM-CSF restored tumor growth in Nt5e knockout tumors, which was reverted by MDSC depletion. Finally, anti-CD73 antibody treatment significantly improved gemcitabine efficacy in orthotopic models. Thus, targeting the adenosine axis presents a novel therapeutic opportunity for improving the anti-tumoral immune response against PDAC. (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze:	MEDLINE
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