As macrophages within the tumor microenvironment can exhibit anti-tumor or pro-tumor effects, modulation of their behavior represents a potential therapeutic approach. This is particularly relevant in the context of ovarian cancer progression where macrophages are a major immune cell population. While the roles of NF-?B signaling in the regulation of tumor-associated macrophages are poorly understood, we have reported that increased NF-?B specifically within macrophages using doxycycline-inducible transgenic mouse models results in significant tumor cell cytotoxicity in the context of mammary or melanoma tumor cells in vivo. We have evidence demonstrating that these effects result from both direct cytotoxic ability and effects on other immune cells. We have begun to gain insights into the roles of NF-?B in ovarian cancer using in vivo models of progression that recapitulate the human disease with significant peritoneal tumor implants and ascites formation. Our findings lead us to believe that direct targeted activation of canonical NF-?B activity in macrophages during defined stages of ovarian tumor progression will induce cytotoxic effects, improve immune responses, and thus decrease tumor load and ascites accumulation. We will use our unique, inducible transgenics to demonstrate the therapeutic potential of increasing macrophage NF-?B activity during ovarian cancer progression. These findings will be used to instruct the optimization and testing of treatments comprised of either liposomally encapsulated MTP-PE (a drug in clinical use for other indications), or of I?B? siRNA delivered specifically to tumor-associated macrophages by nanoparticles. Both of these strategies will increase NF-?B signaling in macrophages and limit disease progression. Our studies will test the hypothesis that increased NF-?B signaling within macrophages in the tumor microenvironment limits tumor progression and synergizes with clinically relevant chemotherapy and thus, represents a novel therapeutic approach. These studies will define the impact of increasing NF-?B signaling specifically in macrophages on the tumor microenvironment and ovarian tumor progression and will show that targeted modulation of NF-?B in macrophages can be harnessed as a novel therapy. These pre-clinical studies will provide critical evidence for a novel immunomodulatory approach alone or combined with relevant chemotherapy for improving ovarian cancer treatment.
A novel immunomodulatory therapy to alter macrophage function in the tumor microenvironment and mediate anti-tumor effects would have significant clinical impact for ovarian cancer, the deadliest gynecologic malignancy. In this proposal, we will use unique doxycycline-inducible transgenics, treatment with a liposomally-encapsulated drug that activates macrophages, and delivery of siRNA specifically to tumor associated macrophages via nanoparticles, to show that increased NF-kappaB signaling, specifically in macrophages, represents such a therapy. These pre-clinical studies will provide critical evidence for clinical development of this immunomodulatory approach either alone or combined with chemotherapy to improve ovarian cancer treatment and ultimately, clinical outcomes.
| Collignon, Evelyne; Canale, Annalisa; Al Wardi, Clémence et al. (2018) Immunity drives TET1 regulation in cancer through NF-?B. Sci Adv 4:eaap7309 |
