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Updated: Oct 7, 2025
Generation of Orthotopic Pancreatic Tumors and Ex vivo Characterization of Tumor-Infiltrating T Cell Cytotoxicity
Published on: December 7, 2019
CD73 induces GM-CSF/MDSC-mediated suppression of T cells to accelerate pancreatic cancer pathogenesis
Ryan J King1, Surendra K Shukla1, Chunbo He1
1The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA.
Abstract:
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.
Insights
Targeting CD73, an enzyme linked to pancreatic cancer growth, reduces tumor aggressiveness and enhances immune response. Inhibiting CD73 decreases immunosuppressive cells and boosts T cell activity, offering a new therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Oncology
- Immunology
- Metabolic pathways
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits poor response to immunotherapy.
- Metabolic alterations significantly influence cancer aggressiveness and immune evasion.
- CD73, an enzyme generating adenosine, is implicated in cancer progression.
Purpose of the Study:
- To investigate the relationship between metabolic alterations, specifically CD73 expression, and the immunosuppressive tumor microenvironment in PDAC.
- To evaluate the therapeutic potential of targeting CD73 in PDAC models.
Main Methods:
- Metabolic enzyme screening in PDAC models.
- Genetic manipulation (knockdown/knockout) of CD73 (encoded by Nt5e).
- Assessment of tumor growth, immune cell populations (MDSCs, T cells), cytokine profiles (GM-CSF, IFN-γ), and response to anti-CD73 antibody treatment combined with gemcitabine.
Main Results:
- Elevated CD73 expression correlates with increased PDAC aggressiveness and interstitial adenosine levels.
- CD73 inhibition reduced tumor growth, decreased myeloid-derived suppressor cells (MDSCs), and lowered GM-CSF.
- CD73 knockdown increased intratumoral CD4+ and CD8+ T cell IFN-γ expression, with CD4+ T cell depletion abrogating therapeutic benefits.
- Targeting CD73 enhanced gemcitabine efficacy in orthotopic PDAC models.
Conclusions:
- CD73-mediated adenosine production promotes PDAC immunosuppression by increasing MDSCs.
- Targeting the CD73-adenosine axis is a promising therapeutic strategy to enhance anti-tumoral immunity in PDAC.
- Combination therapy involving CD73 inhibition may overcome resistance to conventional treatments.
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