Thursday, April 3, 2025
4/3/2025
Cell-Cell Signaling Driving HPV-Induced Respiratory Disease and Vaccine Response - ABSTRACT This patient-centric collaborative translational research project will define cellular and viral biomarkers and mechanisms dictating recurrent respiratory papillomatosis (RRP) patient response to the HPV therapeutic vaccine PRGN-2012. RRP is a debilitating neoplastic disease caused by chronic infection with HPV types 6 and 11 that has no approved medical therapies. A recently published phase 1 clinical trial led by Dr. Clint Allen at the NIH Clinical Center demonstrates that treatment with the gorilla adenovirus-based HPV vaccine PRGN-2012 results in a 50% response rate in patients with severe, aggressive RRP. Our long-term goal is to maximize vaccine treatment effectiveness and confer response in patients who are currently non-responsive. Correlative data limited to pre-treatment papillomas linked the state of the tumor microenvironment to vaccine response. Specifically, response was associated with a) low HPV gene expression, b) low stress keratin 17 (K17) expression, c) high expression of the CD8 T cell chemokines CXCL9-11, and d) prominent CD8 T cell infiltration. Conversely, non-response was associated with a) high HPV gene expression, b) high K17 expression, c) low CXCL9-11 and high neutrophil chemokine CXCL8 expression, and d) prominent neutrophil infiltration with diminished T cell activation. The current proposal greatly expands this correlative clinical data by defining response-related reprogramming in specific epithelial and immune cell subpopulations, extends analysis to paired pre- and post-treatment clinical samples to define phenotypic response outcomes as goals for effective therapy, and tests the hypothesis that high HPV load and gene expression in RRP papilloma epithelial cells attenuates CXCL9-11/CD8 T cell responder phenotypes by inducing K17. We will comprehensively define epithelial and immune cell subpopulations and intercellular signaling using single cell and spatial transcriptomics on pre-treatment and post-treatment papillomas from responders and non-responders collected as a component of the planned prospective phase 3 clinical trial that will power the trial to validate clinical response rates (Aim 1). Complementary mechanistic studies will elucidate the functional role of high vs low HPV gene expression in dictating epithelial phenotypes, cytokine signaling, and immune cell activation and infiltration using isogenic patient-derived organotypic epithelial rafts with low vs high HPV load (Aim 2). Epithelial and immune cell subpopulations and intercellular signaling will be profiled by single cell and spatial transcriptomics for integration with responder and non-responder clinical tissue data. Candidate molecules mediating responder vs non- responder phenotypes, including K17, will be mechanistically tested using pharmacologic, and loss and gain-of- function approaches. These studies unite the epithelial/HPV biology, immunology, pathology, and clinical expertise of an established partnership between Drs. Wells and Wikenheiser-Brokamp at Cincinnati Children’s Hospital and intramural NIH/NCI collaborator Dr. Allen to advance fundamental understanding of RRP pathobiology for development of new treatments that overcome mechanisms of resistance to effective therapies.
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