Pro-Resolving Lipid Mediators and Anti-Angiogenic Therapy Exhibit Synergistic Anti-Tumor Activity via Resolvin Receptor Activation

Inflammation and angiogenesis are interdependent hallmarks of cancer. Tumor growth is angiogenesis-dependent and inflammation is a risk factor for many cancers. Inflammation is regulated by endogenous specialized pro-resolving lipid-autacoid mediators (SPMs), including resolvins, protectins, and maresins, which are present in multiple tissues. Unlike the majority of anti-inflammatory agents, SPMs are non-immunosuppressive, and non-toxic. These lipid autacoids inhibit angiogenesis and clear cellular debris by macrophages resulting in reduced localized inflammatory cytokines. SPMs mediate their pro-resolution and anti-inflammatory activity through at least five known human G-coupled protein receptors (GPR32, GPR18, ChemR23, GPR37, and LGR6) for resolvin (Rv) D1, RvD2, RvE1, protectin D1, and maresin 1, respectively, as well as a murine RvD1 receptor ALX/FPR2. We show that stimulating resolution of inflammation (RvD4 or RvD5) and anti-angiogenic therapy (e.g. the thrombospondin (TSP)-1 peptide 3TSR or anti-VEGF via DC101) induced synergistic antitumor activity in human xenograft models including ovarian cancer (e.g. 36M2) compared with either treatment alone. The triple therapy 3TSR, anti-VEGF, and resolvins displayed additive anti-tumor activity. As the role of SPM receptors in cancer is unknown, we screened various stromal cells in the tumor microenvironment (e.g. macrophages, pericytes, fibroblasts, and neutrophils) for expression of SPM receptors. SPM receptors were expressed in various clinical specimens including breast cancer, head and neck cancer (e.g. oral squamous cell carcinoma), and brain cancer. Flow cytometry and double immunohistochemistry staining confirmed that SPM receptors were expressed in non-tumor cells in the tumor microenvironment (e.g. macrophages, fibroblasts, pericytes and blood vessels) in vivo. Accordingly, SPMs inhibited tumor cell proliferation in vivo. Thus, SPMs exhibit anti-tumor activity via the tumor stroma. Loss of SPM receptor expression may be associated with cancer progression in clinical cancer specimens. Notably, resolvins (RvD4 or RvD5) inhibited tumor growth at doses 10,000 times lower than anti-inflammatory agents such as aspirin and NSAIDs. Thus, stimulating the expression or activity of SPM receptors may enhance current anti-angiogenic therapy for various cancers.