Tumor cell–intrinsic EPHA2 suppresses antitumor immunity by regulating PTGS2 (COX-2)

Resistance to immunotherapy is one of the biggest problems of current oncotherapeutics. While T cell abundance is essential for tumor responsiveness to immunotherapy, factors that define the T cell-inflamed tumor microenvironment are not fully understood. We used an unbiased approach to identify tum...

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Bibliographic Details
Published inThe Journal of clinical investigation Vol. 129; no. 9; pp. 3594 - 3609
Main Authors Markosyan, Nune, Li, Jinyang, Sun, Yu.H, Richman, Lee P, Lin, Jeffrey H, Yan, Fangxue, Quinones, Liz, Sela, Yogev, Yamazoe, Taiji, Gordon, Naomi, Tobias, John W, Byrne, Katelyn T, Rech, Andrew J, FitzGerald, Garret A, Stanger, Ben Z, Vonderheide, Robert H
Format Journal Article
LanguageEnglish
Published Ann Arbor American Society for Clinical Investigation 01.09.2019
Subjects
Adenocarcinoma
Antineoplastic agents
Biomedical research
Bone morphogenetic proteins
Breast cancer
Cancer
Cancer therapies
Clinical trials
Clonal deletion
Cloning
COX-2 inhibitors
Cyclooxygenase-2
EphA2 protein
Gastroenterology
Genes
Genomes
Immunity
Immunosuppression
Immunotherapy
Inflammation
Kinases
Lymphocytes
Lymphocytes T
Medical prognosis
Medical research
Pancreas
Pancreatic cancer
Patients
Phenotypes
Prostaglandins
T cells
Transforming growth factors
Tumor cells
Tumors
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Summary:Resistance to immunotherapy is one of the biggest problems of current oncotherapeutics. While T cell abundance is essential for tumor responsiveness to immunotherapy, factors that define the T cell-inflamed tumor microenvironment are not fully understood. We used an unbiased approach to identify tumor-intrinsic mechanisms shaping the immune tumor microenvironment (TME), focusing on pancreatic adenocarcinoma because it is refractory to immunotherapy and excludes T cells from the TME. From human tumors, we identified ephrin-A receptor 2 (EPHA2) as a candidate tumor-intrinsic driver of immunosuppression. Epha2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy. We found that prostaglandin endoperoxide synthase 2 (PTGS2), the gene encoding cyclooxygenase- 2, lies downstream of EPHA2 signaling through TGF-[beta] and is associated with poor patient survival. Ptgs2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy; pharmacological inhibition of PTGS2 was similarly effective. Thus, EPHA2/PTGS2 signaling in tumor cells regulates tumor immune phenotypes; blockade may represent a therapeutic avenue for immunotherapy-refractory cancers. Our findings warrant clinical trials testing the effectiveness of therapies combining EPHA2/TGF-[beta]/PTGS2 pathway inhibitors with antitumor immunotherapy and may change the treatment of notoriously therapy-resistant pancreatic adenocarcinoma.
Bibliography:Authorship note: NM and JL contributed equally to this work.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI127755