Abstract
Abstract Maintenance of CTL-, Th1-, and NK cell-mediated type-1 immunity is essential for effective anti-tumor responses. Unexpectedly, we observed that IFNγ and TNFα, the critical soluble mediators produced by type-1 immune effector cells, synergize in the induction of cyclooxygenase 2 (COX2), the key enzyme in prostaglandin (PG)E2 synthesis, and the hyper-activation of myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME) of ovarian cancer patients. This MDSC hyper-activation by type-1 immune cells and the subsequent over-expression of indoleamine 2,3-dioxygenase (IDO), inducible nitric oxide synthase (iNOS/NOS2), IL-10, and additional COX2 result in strong feedback suppression of type-1 immune responses. Importantly, this self-limiting feedback could be eliminated by COX2 blockade, allowing amplification of type-1 immunity and prolonged survival of tumor bearing mice. Our data demonstrate a new mechanism underlying the self-limiting nature of type-1 immunity in the human TME and provide rationale for targeting the COX2-PGE2 axis to enhance the effectiveness of cancer immunotherapies.
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