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 (MDSCs) 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, this 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 tumor microenvironment, driven by the synergistic induction of COX2 by IFNγ and TNFα, and provide rationale for targeting the COX2-PGE2 axis to enhance the effectiveness of cancer immunotherapies.
- Received June 30, 2015.
- Revision received November 23, 2015.
- Accepted December 15, 2015.
- Copyright © 2016, American Association for Cancer Research.