Demystifying Tumor-Mediated Local and Systemic Immunosuppression in Pancreatic Ductal Adenocarcinoma

Author

Clara Mundry, University of Nebraska Medical CenterFollow

ORCID ID

0000-0001-8272-5360

Graduation Date

Spring 5-10-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Michael A. Hollingsworth

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that costs many lives every year. Immense immunosuppression at local primary and metastasis sites, as well as the systemic organism, is a hallmark of PDAC that seems a hurdle too insurmountable to overcome. The tumor microenvironment (TME) is characterized by an abundance of anti-inflammatory cytokines, suppressive immune cells, and a hypoxic milieu that renders effector immune cells inactive and fosters further development of immunosuppression. Chapter 1 of this dissertation presents in detail the components that characterize this immunosuppression in the TME as well as within the systemic immunological organs.

The spleen, one of the most important organs for the development and maintenance of a healthy, well-functioning immune system, holds particular significance in PDAC due to its close proximity to the developing tumor. Historically seen as a place for lymphocyte activation and generation of an inflammatory response to infection and malignancy, we have found evidence that the spleen can also be home to immunosuppressive cell types, further contributing to an impaired anti-tumor immune response. Our findings of a tolerogenic, IDO-1-expressing dendritic cell (DC) subtype in the spleen of PDAC patients that stands in vivid communication networks with a plethora of other immune cells are delineated in Chapter 2. This novel splenic DC subset warrants further investigation to parse out the biological significance of the strong interactions between the DCs and other immune cells that potentially are the cause and effect of tumor-derived immunosuppression at the same time.

The main body of work of this dissertation’s projects is presented in Chapters 3 and 4, thoroughly and broadly investigating the influence of tumor cell-derived extracellular vesicles (EVs) on immune cells in PDAC. It has long been known that tumor cells secrete EVs to extend pro-tumoral communication networks within the body and promote tumor progression and metastasis. However, the effects on immune cells, in particular, are understudied. The work presented here is novel, more extensive than ever before, and most certainly essential to deepening our and the field’s understanding of tumor-derived immune-regulating factors in PDAC. We have deciphered the influence of PDAC-derived EVs on the humoral and cellular immune system, with particular emphasis on the role of tumor marker MUC1 on EVs (Chapter 3). Murine PDAC cells (KPC7107), which express MUC1, secrete EVs with strong immunosuppressive effects, whereas EVs from cells lacking MUC1 stimulate the immune system instead. MUC1⁺ EVs are the tumor’s malicious and sneaky messengers, spreading throughout the body and impacting aspects of the adaptive immune system, ranging from antigen presentation to lymphocyte exhaustion to germinal center formation.

We expanded our investigations (1) to study additional immune cell subtypes more thoroughly and, most importantly, (2) to include patient-derived EVs (as described in the last chapter of this thesis). These investigations are just a starting point for future research but significantly elevate the “translationability” and clinical importance of our work. The influence of EVs on NK cells shows a clear immunosuppressive effect on NK cell killing ability in cancer. Initial investigations of marker expression on patient-derived EVs suggest a role of Fas-mediated apoptosis pathways in EV-mediated immunosuppression and propose a relationship between MUC1 and FasR expression on EVs. Most importantly, identifying patient-specific variables in primary samples and clearly defining and delineating heterogeneity in EV composition and effects is essential for ever having even the slightest chance of winning the battle over PDAC.

The following chapters describe in detail the majority of the work that has been done by me in the past five-ish years in the Hollingsworth laboratory. It is a lot for me, a lot for our laboratory, but just so little of what will need to come next. It is humbling and exciting at the same time to think about what this data represents and how many million doors it opens for the future. Let’s start!

Comments

2025 Copyright, the authors

Recommended Citation

Mundry, Clara, "Demystifying Tumor-Mediated Local and Systemic Immunosuppression in Pancreatic Ductal Adenocarcinoma" (2025). Theses & Dissertations. 904.
https://digitalcommons.unmc.edu/etd/904