Using Nucleic Acid Scavengers to Limit Innate Immune Activation on Cancer Cells and Thereby Inhibit Metastasis

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2021

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Breast cancers (BC) remain the most lethal malignancies amongst women. Subtype heterogeneity and aggressive invasion are believed to be major contributors for poor outcomes. Triple negative breast cancers (TNBC) are notoriously aggressive, difficult to treat, pro-inflammatory and highly metastatic. Patients that are diagnosed with localized, surgically resectable tumors are treated with neoadjuvant (preoperative) and adjuvant (post-operative) chemotherapy in the hopes of eliminating micro- and oligo-metastatic disease. However, a majority of these patients progress to metastatic disease even under the selective pressure of our current aggressive therapeutic armament. Tumor metastases to tropic organ sites – primarily the lungs, bones, and brain – can wreak havoc on patients with triple-negative breast cancer. Unfortunately, most patients with metastatic TNBC decline quickly. In order to change the tide against pancreatic cancer and other aggressively metastatic tumor types, there need to be new clinical approaches in the arena of anti-metastatic therapeutics.Tumor metastasis is an incredibly complex process involving interactions between tumor cells, the tumor microenvironment (TME), the surrounding stromal tissues, blood and lymphatic vessels, and the innate and adaptive immune systems. The earliest steps of the metastatic cascade require the tumor cells to undergo the epithelial-to-mesenchymal transition (EMT) in order to have the appropriate morphology, detach from the primary tumor site, invade/intravasate into the stroma and reach the host’s blood or lymphatic vessels in order to travel to distant sites. Even once in the circulation, the tumor cell has to survive the turbulent hemodynamic environment before embedding itself into the distant organ site. Various immune sensors also contribute to this complex interplay, especially the toll-like family of receptors (TLRs). These receptors evolved as a part of the innate immune system to detect pathogen-associated molecular patterns (PAMPs) to combat infectious pathogens including bacteria, fungi and viruses. They can also respond to molecular motifs from self – also known as damage-associated molecular patterns (DAMPs). These receptors are typically expressed by immune cells such as macrophages, dendritic cells, and neutrophils but in recent times have been shown to be expressed on both cancer cells and stromal cells within the tumor. The expression and activation of these receptors by either PAMPs and/or DAMPs has been implicated in tumor progression and metastasis in a variety of solid and hematologic malignancies. Going beyond their utility to act as universal antidotes for aptamers (which was already beyond their initial purpose as gene delivery tools), our lab previously discovered that a subset of nucleic-acid binding polymers (NABPs) could behave as nucleic -acid scavengers (NAS). Previously we determined that NASs can block metastatic signals elicited by nucleic acid-containing damage-associated molecular patterns (NA DAMPs) in the pancreatic cancer setting. By behaving as anti-inflammatory compounds scavenging extracellular nucleic acids and associated protein complexes that promote pathological activation of TLRs, our lab demonstrated their efficacy in various murine models of disease including systemic lupus erythematosus, sepsis, and influenza infection. Nucleic-acid mediated TLR signaling also facilitates tumor progression and metastasis in several malignancies, including pancreatic cancer and breast cancer. In the first part of this dissertation, we observe that TNBC cells express TLR9, are responsive to TLR9 ligands, and treatment of TNBC cells with chemotherapy increases the release of such NA DAMPs in culture. Chemotherapy derived and BC-patient derived DAMPs increase TLR9 activation and TNBC cell invasion in vitro; however, treatment with the NAS PAMAM-G3 significantly counteracts such effects. NAS treatment in a spontaneous BC murine model (MMTV-PyMT) also led to diminished lung metastatic burden. Thus, NAS may prove useful for inhibiting pathological processes (e.g. metastasis) and represent a novel combination therapeutic approach. The second part of this dissertation, we focused on a clinical descriptive project whereby we took plasma from breast cancer patients pre- and post-neoadjuvant chemotherapy. Our goal was to get an overview of the immune landscape in these patients and if there was any functional consequence of chemotherapy treatment on invasive potential in vitro. While the work shows promise, it really is laying down the groundwork for better understanding what immune mediators are upregulated upon standard-of-care therapies. The last part of this dissertation covers ongoing projects that I started but was unable to bring all the way to publication. Among these are the optimization of cytokine arrays using monocytes and various sources of in vitro or ex vivo NA DAMPs. I also detail a little of the work we carried out building the immune panels to better track and interrogate antigen-tagged pancreatic cancer cells and where they metastasize as well as the effect of PAMAM-G3 in our murine models of cancer. And finally, a small vignette concerning the role of cancer-associated tumor thrombosis and how we can utilize the highly pro-thrombotic KPC pancreatic cancer mouse model to be imaged via a fluorescence labeled thrombin aptamer.

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Eteshola, Elias (2021). Using Nucleic Acid Scavengers to Limit Innate Immune Activation on Cancer Cells and Thereby Inhibit Metastasis. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/23738.

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