Immunological Impacts of VIP and PDL1 Double Knockout in Mice Open Access

Abstract

Vasoactive intestinal peptide (VIP) is an immunosuppressive protein overexpressed by pancreatic adenocarcinoma (PDAC) that suppresses T-cell responses. Combination treatment inhibiting both the VIP pathway and the protein death ligand-1 (PDL1) pathway has been shown to generate synergistic anticancer responses. To study the mechanistic basis for the synergy observed targeting VIP and PDL1 signaling, this study generates VIP PDL1 double knockout (DKO) mice and characterizes their immunology. Previous DKO mice targeting two immune checkpoints have resulted in compromised immune tolerance and led to autoimmune-related deaths.  However, this study generated viable and healthy VIP PDL1 DKO by crossing VIP KO and PDL1 KO mice with a modulated immune system at ratios consistent with Mendelian frequencies and no autoimmune-related lethality. Under normal physiological conditions, we did not observe evidence of autoimmunity in the VIP PDL1 DKO mice. We then tested their ability to reject a transplantable PDAC cell line. The VIP PDL1 DKO had heightened anti-cancer responses with better survival and slower tumor growth rates when compared to single knockouts. In conclusion, these finding gives rationale to target both the VIP and PDL1 pathways as a potent therapeutic approach against PDAC with limited off-cancer toxicity. 

Table of Contents

Introduction                                                                                                                          1

Methods                                                                                                                                 2

Results                                                                                                                                   4

Discussion                                                                                                                             8

References                                                                                                                            11

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Health Sciences, Oncology Health Sciences, Immunology
Keyword	Vasoactive Intestinal Peptide Pancreatic Cancer Protein Death Ligand-1 Cancer Immunotherapy
Committee Chair / Thesis Advisor	Dr. Edmund K. Waller, Emory University
Committee Members	Dr. David Civitello, Emory University Dr. Cindy Giver, Emory University

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