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Tumor cell-intrinsic EPHA2 suppresses antitumor immunity by regulating PTGS2 (COX-2)
- Source :
- Journal of Clinical Investigation. September, 2019, Vol. 129 Issue 9, p3594, 16 p.
- Publication Year :
- 2019
-
Abstract
- 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.<br />Introduction Immunotherapies, including immune checkpoint blockade (ICB), have led to significant improvement of clinical care for cancer patients (1-4). Patients with melanoma, lung adenocarcinoma, or kidney cancer have a 20%-40% [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 129
- Issue :
- 9
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.600664901
- Full Text :
- https://doi.org/10.1172/JCI127755