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

Oncogene volume 41, pages 971–982 (2022)Cite this article

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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.

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Fig. 1: NT5E is overexpressed and impacts survival in pancreatic cancer.
Fig. 2: Decreased CD73 improves survival and decreases tumor burden.
Fig. 3: Tumoral Nt5e expression regulates GM-CSF, T cells, and MDSCs.
Fig. 4: Nt5e knockdown facilitates CD4+ T cell-mediated anti-tumor immune response.
Fig. 5: Decreased tumor burden by CD73 knockouts is rescued by GM-CSF supplementation, and the effect is abolished by MDSC depletion.
Fig. 6: Gemcitabine and anti-CD73 combination therapy diminish tumor burden and improves survival.

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Acknowledgements

We would like to thank the University of Nebraska Medical Center Rapid Autopsy Pancreatic Program and the patients who generously donated their samples.

Funding

This work was supported in part by funding from the National Institutes of Health grant (R01CA163649, R01CA210439, and R01CA216853, NCI) to PKS; the Specialized Programs of Research Excellence (SPORE, 2P50 CA127297, NCI) to PKS and MAH; SPORE Career Development Award (2P50 CA127297, NCI) to KM; the PCDC U01CA210240 to MAH; NCI Research Specialist award (5R50CA211462) to PMG. We would also like to acknowledge the Fred & Pamela Buffett Cancer Center Support Grant (P30CA036727, NCI) for supporting shared resources.

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  1. These authors contributed equally: Surendra K. Shukla, Chunbo He.

Authors and Affiliations

  1. The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 68198, Omaha, NE, USA

    Ryan J. King, Surendra K. Shukla, Chunbo He, Enza Vernucci, Ravi Thakur, Kuldeep S. Attri, Aneesha Dasgupta, Nina V. Chaika, Scott E. Mulder, Jaime Abrego, Divya Murthy, Venugopal Gunda, Camila G. Pacheco, Paul M. Grandgenett, Michael A. Hollingsworth, Kamiya Mehla & Pankaj K. Singh

  2. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 68198, Omaha, NE, USA

    Scott E. Mulder, Michael A. Hollingsworth & Pankaj K. Singh

  3. Department of Pathology and Microbiology, University of Nebraska Medical Center, 68198, Omaha, NE, USA

    Audrey J. Lazenby, Michael A. Hollingsworth & Pankaj K. Singh

  4. Department of Biostatistics, University of Nebraska Medical Center, 68198, Omaha, NE, USA

    Fang Yu

  5. Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, 68198, Omaha, NE, USA

    Pankaj K. Singh

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  1. Ryan J. King
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Contributions

RK, PKS, KM conceived the idea and designed the study. SKS, CH, EV, RT, KSA, AD, NVC, SEM, JA, DM, VG, CGP, and KM participated in experiments. RK, SKS, CH, NVC, VG, and KM analyzed the results. FY provided statistical assistance. RK performed bioinformatics. VG ran the mass spectrometer. NVC and AJL provided pathology assistance. PMG and MAH provided patient samples. RK drafted the manuscript. PKS, CH, SKS, KSA, SEM, JA, DM, and KM reviewed the manuscript and made thorough revisions on the draft.

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Correspondence to Kamiya Mehla or Pankaj K. Singh.

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King, R.J., Shukla, S.K., He, C. et al. CD73 induces GM-CSF/MDSC-mediated suppression of T cells to accelerate pancreatic cancer pathogenesis. Oncogene 41, 971–982 (2022). https://doi.org/10.1038/s41388-021-02132-6

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