Abstract
ABSTRACTReprogramming of immunosuppressive tumor microenvironment (TME) by targeting alternatively activated tumor associated macrophages (M2TAM), myeloid-derived suppressor cells (MDSC), and regulatory T cells (Tregs), represents a promising strategy for developing novel cancer immunotherapy. Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite and mediator of chronic inflammation, has emerged as a powerful immunosuppressor in the TME through engagement with one or more of its 4 receptors (EP1-EP4). We have developed E7046, an orally bioavailable EP4-specific antagonist and show here that E7046 has specific and potent inhibitory activity on PGE2-mediated pro-tumor myeloid cell differentiation and activation. E7046 treatment reduced the growth or even rejected established tumors in vivo in a manner dependent on both myeloid and CD8+ T cells. Furthermore, co-administration of E7046 and E7777, an IL-2-diphtheria toxin fusion protein that preferentially kills Tregs, synergistically disrupted the myeloid and Treg immunosuppressive networks, resulting in effective and durable anti-tumor immune responses in mouse tumor models. In the TME, E7046 and E7777 markedly increased ratios of CD8+granzymeB+ cytotoxic T cells (CTLs)/live Tregs and of M1-like/M2TAM, and converted a chronic inflammation phenotype into acute inflammation, shown by substantial induction of STAT1/IRF-1 and IFNγ-controlled genes. Notably, E7046 also showed synergistic anti-tumor activity when combined with anti-CTLA-4 antibodies, which have been reported to diminish intratumoral Tregs. Our studies thus reveal a specific myeloid cell differentiation-modifying activity by EP4 blockade and a novel combination of E7046 and E7777 as a means to synergistically mitigate both myeloid and Treg-derived immunosuppression for cancer treatment in preclinical models.
Highlights
Checkpoint inhibitors have produced impressive therapeutic effects in cancer patients, but far, only a fraction of patients benefit from this class of cancer immunotherapies
E7046 reversed the immunosuppressive effects of Prostaglandin E2 (PGE2) on activation and differentiation of human myeloid cells through selective prostaglandin E2 receptor 4 (EP4) antagonism
This system consists of cocultures of primary human peripheral blood mononuclear cells (PBMC), or purified macrophages, with endothelial cells in conditions that stimulate T cell receptor (TCR), or activate either M2TAM or M1 macrophages, allowing a systematic examination of numerous immune readouts including leukocyte proliferation, cytotoxicity, and production of cytokines and chemokines, adhesion molecules, and enzymes (Supplementary Fig. S2A)
Summary
Checkpoint inhibitors have produced impressive therapeutic effects in cancer patients, but far, only a fraction of patients benefit from this class of cancer immunotherapies. It is of great interest to develop novel immunotherapies and combinations to increase patient responsiveness. In this regard, reprogramming of the immunosuppressive TME by targeting myeloid-derived suppressor cells (MDSC), M2TAMs, and Tregs represents an important approach to developing novel cancer immunotherapies. The relative contribution of each of these EP receptors in mediating the immunosuppressive effect of PGE2 has not been fully elucidated and some reports even show opposing activities of EP receptors on immune function.[3] EP4, a Gas protein coupled receptor expressed mainly on myeloid cells, T lymphocytes, and tumor cells[4] has emerged as a major contributor to PGE2mediated enhancement of tumor survival pathways and as a suppressor of innate and adaptive anti-tumor immune
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