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Generation of Orthotopic Pancreatic Tumors and Ex vivo Characterization of Tumor-Infiltrating T Cell Cytotoxicity
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Disrupting a converging metabolic target turns up the immunologic-heat in pancreatic tumors

Won Jin Ho1,2, Elizabeth M Jaffee1,2,3,4,5

  • 1Sidney Kimmel Comprehensive Cancer Center.

The Journal of Clinical Investigation
|December 4, 2019
PubMed

Insights

Pancreatic cancer (PDAC) is often unresponsive to immunotherapy due to its immunosuppressive tumor microenvironment. A novel glutamine antagonist, DON, converts PDAC tumors into a "hot" microenvironment, enhancing immunotherapy effectiveness.

Area of Science:

  • Oncology
  • Immunology
  • Metabolic pathways

Background:

  • Pancreatic ductal adenocarcinomas (PDACs) are characterized as "cold" tumors, exhibiting limited response to immunotherapy.
  • The immunosuppressive tumor microenvironment (TME) and dense stromal barrier in PDACs impede immune cell infiltration and function.

Purpose of the Study:

  • To investigate the efficacy of targeting a shared metabolic pathway in PDAC growth and hyaluronan production.
  • To explore the potential of converting the PDAC TME into an immunologically "hot" state.

Main Methods:

  • Utilized 6-diazo-5-oxo-l-norleucine (DON), a broad glutamine antagonist.
  • Assessed the impact of DON on PDAC growth, hyaluronan production, and TME characteristics.

Main Results:

  • DON targets a metabolic program crucial for both PDAC proliferation and hyaluronan synthesis.
  • The treatment demonstrated a conversion of the PDAC TME from "cold" to "hot".

Conclusions:

  • Targeting glutamine metabolism with DON can remodel the PDAC TME.
  • This approach shows promise for enhancing the efficacy of immunotherapeutic strategies, including anti-PD1 therapy, in pancreatic cancer.

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