Tumors that express the protein indoleamine 2,3-dioxygenase (IDO1) constitutively respond to the cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex®) and have increased infiltration of certain T-cell subsets making them more responsive to anti-PD1 treatment, according to study results published in the journal Cancer Immunology Research.
Many tumor cells are resistant to immunotherapy due to IDO1 expression. In adaptive resistance, the tumor cells starts to produce IDO1 — which is associated with inflammation and T-cell infiltration — upon T-cell attack. In intrinsic resistance, the tumor cell produces IDO1 constitutively (continuously) which prevents T-cell infiltration completely.
Benoit J. Van den Enyde, MD, PhD, the author of the report, and colleagues demonstrated that constitutive IDO1 expression via MAPK, PKC, and PI3K cell-signaling pathways was caused by COX-2 and prostaglandin E2 (PGE2). Researchers were then able to show that tumor cells with constitutive IDO1 expression had similar responses to both celecoxib and epacadostat, an IDO1 inhibitor.
Depending on tumor type, initial analysis showed that IDO1 was constitutively expressed by 10% to 50% of human tumors. IDO1 expression and COX-2/PGE2 axis activation were found to be associated in numerous cancer types, including lung cancer, liver, pancreatic, stomach, and sarcoma.
Dr Van den Enyde concluded saying, “Our studies provide a clear rationale to test, in the clinics, combinations of anti-PD1 immunotherapy and COX-2 inhibitors.”
1. COX-2 inhibitors may reverse IDO1-mediated immunosuppression in some cancers [news release]. Philadelphia, PA: American Association of Cancer Research; July 21, 2017. http://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1070#.WXIDpYTytOQ. Accessed July 21, 2017.