Functions of TIE2-Expressing Macrophages in Pancreatic Ductal Adenocarcinoma and Their Role in Neoadjuvant Chemotherapy Response

Abstract public domain (NIH RePORTER)

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a notoriously devastating cancer with a low survival rate and marked therapeutic resistance. While the mainstay treatment is surgical resection, neoadjuvant chemotherapy (NAC) is often administered to downstage the tumor prior to surgery. However, NAC is not effective in all patients. “Responders” and “non-responders” are categorized based on histopathologic score of the tumor at resection and circulating CA19-9 levels in blood. Patients who respond to NAC have better surgical outcomes and survival than those who do not. The cause of different NAC responses between patients remains unclear. Therefore, identification of NAC resistance mechanisms is vital. PDAC pathogenesis and treatment response is impacted by its characteristic tumor microenvironment, which is immunosuppressive, fibrotic, hypovascular, and hypoxic. A subset of tumor-associated macrophages (TAMs), called TIE2-expressing macrophages/monocytes (TEMs), are linked to decreased survival in PDAC patients after surgery. TEMs express the TIE2 receptor typically found on endothelial cells and have been explored functionally in the context of other cancers but not in PDAC. TEMs may function in immunosuppression through secretion of IL-10 and CCL17, which inhibit pro-inflammatory CD8+ T cells (CTLs) and promote anti-inflammatory regulatory T cells (Tregs). TEMs also function in dysfunctional vessel remodeling through vascular endothelial growth factor (VEGF) secretion. Importantly, TEM-mediated vessel remodeling results in decreased vessel function and has been linked to the creation of sites within vessels through which tumor cells can intravasate and metastasize to other sites. The objective of this application is to utilize a bedside-to-bench approach to elucidate PDAC-specific pathological functions of TEMs and correlate those findings to NAC responder status. Our central hypothesis is that TEMs mediate immunosuppressive effects and promote dysfunctional vessel remodeling in PDAC, and these functions interact with NAC to yield overall patient NAC response. Aim 1 will investigate the immunosuppressive functions of circulating and tumor- infiltrating TEMs, with a focus on cytokine-mediated changes in T cell populations. Aim 2 will assess a regulatory role for TEMs in blood vessel function with a focus on PDAC hypovascularity by spatial transcriptomics with protein expression and localization of hypoxic zones and functional vessels relative to TEMs. This work is impactful because it will identify the role of a subset of macrophages likely contributing to PDAC treatment resistance. The findings of this study can be applied to the long-term goals of improving treatment responses and identifying new therapeutic targets in PDAC. The proposed training plan utilizes approaches that span the translational research continuum, including a mix of patient samples and genetic mouse models, flow cytometry, immunohistochemistry, Visium spatial transcriptomics with protein expression, murine survival surgery, and tracking of murine tumors by magnetic resonance imaging (MRI). Experience gained in the proposed study will advance my professional goals of becoming an independent physician scientist specializing in immuno-oncology.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreatic cancer is deadly and difficult to treat. A subset of immune cells, called TIE2-expressing macrophages (TEMs), have not been studied functionally in pancreatic cancer but are known to be tumor-supportive in other tumor types and are linked with decreased recurrence-free survival after surgery in pancreatic cancer. This proposal will explore how TEMs function in pancreatic cancer and contribute to neoadjuvant chemotherapy response, with long-term goals being identifying TEMs as a therapeutic target, improving responses to current treatments, and increasing the likelihood of positive outcomes in patients.