Synergistic COX2 Induction by IFNγ and TNFα Self-Limits Type-1 Immunity in the Human Tumor Microenvironment

• Published in: Cancer immunology research Vol. 4; no. 4; p. 303
• Main Authors: Wong, Jeffrey L, Obermajer, Nataša, Odunsi, Kunle, Edwards, Robert P, Kalinski, Pawel
• Format: Journal Article
• Language: English
• Published: United States 01.04.2016
• Subjects: Biomarkers; Cyclooxygenase 2 - biosynthesis; Cytokines - metabolism; Dinoprostone - metabolism; Female; Humans; Immunity; Immunomodulation; Interferon-gamma - metabolism; Lymphocyte Activation; Myeloid Cells - immunology; Myeloid Cells - metabolism; Neoplasm Staging; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Ovarian Neoplasms - immunology; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Tumor Microenvironment - immunology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 2326-6074
• DOI: 10.1158/2326-6066.CIR-15-0157

Maintenance of CTL-, Th1-, and NK cell-mediated type-1 immunity is essential for effective antitumor responses. Unexpectedly, we observed that the critical soluble mediators of type-1 immune effector cells, IFNγ and TNFα, synergize in the induction of cyclooxygenase 2 (COX2), the key enzyme in prostaglandin (PG)E2 synthesis, and the subsequent hyperactivation of myeloid-derived suppressor cells (MDSC) within the tumor microenvironment (TME) of ovarian cancer patients. MDSC hyperactivation by type-1 immunity and the resultant overexpression of indoleamine 2,3-dioxygenase (IDO), inducible nitric oxide synthase (iNOS/NOS2), IL10, and additional COX2 result in strong feedback suppression of type-1 immune responses. This paradoxical immune suppression driven by type-1 immune cell activation was found to depend on the synergistic action of IFNγ and TNFα, and could not be reproduced by either of these factors alone. Importantly, from a therapeutic standpoint, these negative feedback limiting type-1 responses could be eliminated by COX2 blockade, allowing amplification of type-1 immunity in the ovarian cancer TME. Our data demonstrate a new mechanism underlying the self-limiting nature of type-1 immunity in the human TME, driven by the synergistic induction of COX2 by IFNγ and TNFα, and provide a rationale for targeting the COX2-PGE2 axis to enhance the effectiveness of cancer immunotherapies.