Fine-Tuning Fate: VIP and VIP Receptors as Dynamic Rheostats in Pancreatic Cancer Restricted; Files Only
Tenzin Passang Lim (Summer 2024)
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly disease of the pancreas with limited treatment options. While significant efforts have contributed to our understanding of the disease pathogenesis and progression, the complex interplay between the cellular and non-cellular components in PDAC tumor microenvironment (TME) is only beginning to be comprehended. The disease is further complicated by its poor or lack of clinical response to currently available immune checkpoint blockade therapies. Such recalcitrant nature of the disease, therefore, signifies an urgent need to understand the mechanisms leading to escape from immune-mediated destruction. Previously, we have shown that PDAC overexpress vasoactive intestinal peptide (VIP) and that the antagonisms of VIP signaling enhance response to anti-PD1 therapy in various PDAC mouse models. VIP is a neuropeptide well known for its immunosuppressive effects on the immune system. However, the cellular mechanisms of VIP underlying its role in the TME are poorly understood. More importantly, it is unclear which of the two receptors, VPAC1 or VPAC2 receptor, are responsible for downstream VIP signaling within the PDAC TME. The primary objective of the research presented in this dissertation was to determine the role of VIP and VIP receptors as a critical immune regulatory pathway exploited by cancer cells and immune cells in the TME. Within these mechanisms, pathological expression of VIP by the cancer cells leads to autocrine signaling via the VPAC2 receptor while facilitating mono/mac expression of VIP in a positive feed-forward loop to drive PDAC tumor growth and immune suppression in the TME. Using in vivo mouse models, patient-derived blood, and single-cell sequencing technology, we determine an abundance of VIP-expressing myeloid population rendering immunosuppressive phenotypes that further lead to T cell inhibition in the TME, the phenomenon that can be reversed upon VIP receptor antagonism. Together, these results from murine and human studies highlight an essential role of the VIP pathway in potentiating tumor growth and immune escape in PDAC. The clinical development of our lead VIP receptor antagonist, ANT308, for its use in combination with existing or emerging therapeutics, may provide a much-needed therapeutic strategy for treating and managing pancreatic cancer.
Table of Contents
Chapter 1: Introduction...................................................................................................................................................................1 - 23
1-1 Solid Malignancies and Cancer Immunotherapy ......................................................................................................................2 - 9
1-1.1 Overview of Cancer Immunotherapy .......................................................................................................................................2
1-1.2 Rise of T-cell Checkpoint Therapies in Solid Malignancies ........................................................................................................7
1-1.2 Current Challenges ................................................................................................................................................................8
1-2 Pancreatic Ductal Adenocarcinoma .....................................................................................................................................10 - 14
1-2.1 Overview of the Disease ........................................................................................................................................................10
1-2.2 Therapeutic Options .............................................................................................................................................................11
1-2.3 Current Challenges ...............................................................................................................................................................13
1-3 Vasoactive Intestinal Peptide and Its Receptors ....................................................................................................................15 - 23
1-3.1 Overview of VIP and VIP-Receptor Signaling ..........................................................................................................................15
1-3.2 Role of VIP (T, Macrophages, DCs) .........................................................................................................................................17
1-3.3 VIP in Cancer .......................................................................................................................................................................20
Chapter 2: VPAC2 Receptor Signaling Promotes Growth and Immunosuppression in Pancreatic Cancer ...............................................24 - 67
2-1 Abstract ..................................................................................................................................................................................25
2-2 Introduction.............................................................................................................................................................................25
2-3 Materials and Methods..............................................................................................................................................................27
2-4 Results.....................................................................................................................................................................................35
2-5 Discussion ...............................................................................................................................................................................44
2-6 Figure Legends .........................................................................................................................................................................49
2-7 Figures ....................................................................................................................................................................................56
Chapter 3: VIP Supports Suppressive TAMs via VPAC1 Receptor Signaling and Facilitates PDAC Tumor Growth.....................................68 - 99
3-1 Abstract ...................................................................................................................................................................................69
3-2 Introduction..............................................................................................................................................................................69
3-3 Materials and Methods...............................................................................................................................................................72
3-4 Results......................................................................................................................................................................................78
3-5 Discussion ................................................................................................................................................................................86
3-6 Figure Legends ..........................................................................................................................................................................90
3-7 Figures .....................................................................................................................................................................................93
Chapter 4: Cell-Intrinsic Role of VIP on T cell Suppression and Survival is Differentially Regulated by VIP Receptors ............................100 - 122
4-1 Abstract ...................................................................................................................................................................................101
4-2 Introduction............................................................................................................................................................................. 101
4-3 Materials and Methods ..............................................................................................................................................................103
4-4 Results......................................................................................................................................................................................104
4-5 Discussion ................................................................................................................................................................................108
4-6 Figure Legends .........................................................................................................................................................................112
4-7 Figures .....................................................................................................................................................................................115
Chapter 5: Therapeutic Intervention to Target VIP-Receptor Signaling ...............................................................................................123 - 145
5-1 Abstract ................................................................................................................................................................................... 124
5-2 Introduction..............................................................................................................................................................................124
5-3 Materials and Methods ...............................................................................................................................................................126
5-4 Results.......................................................................................................................................................................................127
5-5 Discussion .................................................................................................................................................................................133
5-6 Figure Legends ...........................................................................................................................................................................137
5-7 Figures .......................................................................................................................................................................................139
Chapter 6: Putting It Together ...........................................................................................................................................................146 - 154
6-1 Summary.................................................................................................................................................................................... 147
6-2 Conclusions and Perspectives .......................................................................................................................................................149
6-3 Future Directions ........................................................................................................................................................................151
6-4 Working Model ........................................................................................................................................................................... 154
References .......................................................................................................................................................................................155 - 169
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