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Breaking barriers for T cells by targeting the EPHA2/TGF-β/COX-2 axis in pancreatic cancer.

Publication ,  Journal Article
Conejo-Garcia, JR
Published in: J Clin Invest
July 29, 2019

Pancreatic ductal adenocarcinoma is projected to become the second leading cause of cancer-related death and is largely resistant to immunotherapies. The tumor microenvironment, largely composed of heterogeneous myeloid cells, creates a physical, metabolic, and immunosuppressive barrier that prevents T cells from infiltrating cancer beds. In this issue of the JCI, Markosyan and colleagues have reported a tumor-intrinsic mechanism that excludes T cells from the vicinity of tumor cells. They showed that a receptor tyrosine kinase, ephrin-A receptor 2 (EPHA2), regulates prostaglandin endoperoxide synthase 2 (PTGS2) (encodes COX-2) expression in a TGF-β signaling-dependent manner. Genetic ablation of Epha2 or Ptgs2 in preclinical models or pharmacological inhibition of COX-2 elicited the transformation of this immunosuppressive microenvironment into a T cell-permissive milieu. Consequent T cell relocation rendered this immunoresistant malignancy responsive to combinations of checkpoint blockers and CD40 agonists. Because the association between T cell infiltration and the EPHA2/TGF-β/COX-2 axis is supported by independent clinical data, these results provide a rationale for ensuing clinical trials aimed at incorporating pancreatic cancer into the range of immunotherapy-responsive tumors.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

July 29, 2019

Volume

129

Issue

9

Start / End Page

3521 / 3523

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • T-Lymphocytes
  • Pancreatic Neoplasms
  • Immunology
  • Humans
  • Cyclooxygenase 2
  • Carcinoma, Pancreatic Ductal
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
  • 31 Biological sciences
 

Citation

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Conejo-Garcia, J. R. (2019). Breaking barriers for T cells by targeting the EPHA2/TGF-β/COX-2 axis in pancreatic cancer. J Clin Invest, 129(9), 3521–3523. https://doi.org/10.1172/JCI130316
Conejo-Garcia, Jose R. “Breaking barriers for T cells by targeting the EPHA2/TGF-β/COX-2 axis in pancreatic cancer.J Clin Invest 129, no. 9 (July 29, 2019): 3521–23. https://doi.org/10.1172/JCI130316.
Conejo-Garcia JR. Breaking barriers for T cells by targeting the EPHA2/TGF-β/COX-2 axis in pancreatic cancer. J Clin Invest. 2019 Jul 29;129(9):3521–3.
Conejo-Garcia, Jose R. “Breaking barriers for T cells by targeting the EPHA2/TGF-β/COX-2 axis in pancreatic cancer.J Clin Invest, vol. 129, no. 9, July 2019, pp. 3521–23. Pubmed, doi:10.1172/JCI130316.
Conejo-Garcia JR. Breaking barriers for T cells by targeting the EPHA2/TGF-β/COX-2 axis in pancreatic cancer. J Clin Invest. 2019 Jul 29;129(9):3521–3523.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

July 29, 2019

Volume

129

Issue

9

Start / End Page

3521 / 3523

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • T-Lymphocytes
  • Pancreatic Neoplasms
  • Immunology
  • Humans
  • Cyclooxygenase 2
  • Carcinoma, Pancreatic Ductal
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
  • 31 Biological sciences