Abstract P3-01-03: Modulating inflammation with nucleic acid scavengers to prevent breast cancer metastasis

Abstract

Abstract Rationale: Chronic inflammation is a hallmark of cancer. Inflammation, whether it is an underlying baseline condition or induced/exacerbated due to treatment, is a major hurdle that ultimately impacts the efficacy of standard of care therapy. However, no strategy exists to effectively control endogenous or therapy-induced inflammation in women with breast cancer. Moreover, there is limited information on how endogenous or therapy-induced inflammation modulates immune cells in women with breast cancer. Nucleic acid-containing pro-inflammatory complexes, termed Nucleic Acid-containing Damage Associated Molecular Patterns (NA-DAMPs), are released from dead or dying cancer cells or activated immune cells. NA-DAMPs activate nucleic acid sensing toll-like receptors (TLR) and other pattern recognition receptors (PRR). NA-DAMPs promote tumor progression and metastasis by inducing pro-tumorigenic signaling in cancer cells. Excessive and persistent NA-DAMP-mediated PRR signaling in immune cells is associated with immune dysfunction. Nucleic acid binding polymers have been used as vehicles for DNA/RNA delivery. We have discovered that a subset of nucleic acid binding polymers, termed nucleic acid scavengers (NAS), act as anti-inflammatory agents by capturing cancer-promoting pro-inflammatory NA-DAMPs. Therefore, we investigated if a NAS could limit cancer progression and metastasis by capturing and mitigating the effects of NA-DAMPs in immunocompetent murine models of breast cancer. Methods: We tested the use of the NAS PAMAM-G3 in the 1] orthotopic surgical resection 4T1 breast cancer model; 2] intravenous experimental metastasis 4T1 breast cancer model; 3] MMTV-PyMT spontaneous breast cancer model. We also measured changes in inflammation/inflammatory cell profile in tumor and in blood. Next, we investigated the relationship between therapy, NA-DAMPs and immune cell profile in blood from women with breast cancer. We also examined if NA-DAMPs in patient serum induces tumor invasion and if the NAS PAMAM-G3 prevents tumor invasion using an in vitro assay. Results: We have determined that the NAS PAMAM-G3 controls lung metastasis in immunocompetent murine models of breast cancer and our data indicate that: 1] chronic inflammation and inflammatory cells in the tumor and periphery promote cancer invasion and metastasis; 2] modulating inflammation by removing excessive NA-DAMPs using the NAS PAMAM-G3 limits cancer metastasis; 3] scavenging inflammation-associated NA-DAMPs significantly alters immune cell and cytokine/chemokine profile in the tumor and periphery, promotes T cell infiltration in the tumor and induces antitumor CD8+ T cell responses. In experiments conducted using blood collected longitudinally from women undergoing standard of care therapy, we observed that: 1] NA-DAMPs and inflammatory monocytes are elevated in women undergoing standard of care therapy; 2] Post-chemotherapy breast cancer patient serum increases invasion/migration of human breast cancer cells in vitro; 3] PAMAM-G3 abrogates increase in invasion/migration of human breast cancer cells in vitro in response to post-chemotherapy breast cancer patient serum. Conclusions: These results highlight the potential utility of NAS to treat cancer associated inflammation and thereby inhibit cancer metastasis by 1) limiting extracellular NA-DAMP-induced persistent activation of pro-inflammatory signaling, and 2) promoting full engagement of both the innate and adaptive immune systems. These principles will aid in the development of a novel anti-metastatic therapy for women with breast cancer. This work is supported by Department of Defense Breast Cancer Research Program Awards W81XWH-16-1-0512 (Nair) and W81XWH-16-1-0513 (Sullenger). Citation Format: Smita Nair, Eda Holl, Karenia Landa, Victoria Frazier, Elias Eteshola, David Boczkowski, Rachel Rempel, Shelley Hwang, Bruce Sullenger. Modulating inflammation with nucleic acid scavengers to prevent breast cancer metastasis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-01-03.