Document text
Principal Investigator: Hyo Sik Jang
Organization: VAN ANDEL RESEARCH INSTITUTE
Fiscal Year: 2024
Award: $153,160
Funding agency: National Cancer Institute
PROJECT SUMMARY
One hallmark of cancer is a tumor’s ability to evade immune detection and elimination. Immune checkpoint
inhibitors (ICIs) are an attractive therapeutic strategy for many cancers. After many clinical trials targeting various
solid cancer types, however, only 15-40% of patients benefited from ICI therapy. Shockingly, 4-29% of non-
responsive patients developed hyperprogressive disease (HPD), a condition characterized by accelerated tumor
growth and rapid clinical deterioration. Very little is known about what causes HPD or how to prevent it, but
recent work suggests that tumor hyperproliferation is an immune-related adverse event (irAE). As part of the
VAI-SU2C Epigenetic Dream Team, we discovered that activating the aryl hydrocarbon receptor (AHR) pathway
and its downstream target gene CYP1A1 are prognostic indicators for the hyperproliferative-irAE (HP-irAE), and
that HP-irAE bladder tumors show a metabolic switch towards fatty acid and xenobiotic metabolism. AHR is
known to have an oncogenic role in tumorigenesis and immune dysfunction, which leads to the working
hypothesis that AHR activation before ICI therapy preconditions the cancer cells or tumor microenvironment for
rapid proliferation, where HP-irAE is then triggered by intracellular PD-L1 signaling in immune cells and/or cancer
cells after ICI therapy. To test this hypothesis, we will first use the NanoString GeoMX platform to spatially profile
RNA and protein expression in CYP1A1-positive bladder tumor microenvironments to resolve the spatial
heterogeneity of immune and cancer cell dependencies (Aim 1). In Aim 2, we will determine how ICI treatment
and AHR activation transcriptionally and metabolically reprograms bladder cancer and immune cells. These
experiments will separate the cancer-intrinsic, immune-related, and metabolic consequence of AHR and PD-L1
signaling, and provide powerful models for future genetic- or drug-screening studies. Finally (Aim 3), we will use
a bladder cancer mouse models to define how AHR and ICI treatment impacts the evolution of the tumor
microenvironment in vivo. These data will provide valuable insight into how AHR activation might influence ICI
efficacy and adverse events. The K99 phase of this project will provide vital training in spatial
transcript/proteomics, metabolomics, and multimodal single-cell technologies, and how to process and integrate
high-dimensional data to understand (bladder) cancer evolution and irAEs. This effort will be guided by an
outstanding, multidisciplinary advisory committee, led by Dr. Peter Jones at Van Andel Institute, that amalgamate
basic and translational science across cancer biology, immunology, epigenetic, and metabolism fields. These
training and new skill sets will be leveraged to ultimately transition into an independent research career (R00
phase) and validate in vitro findings with in vivo mouse models. Together, this project will provide the first
mechanistic insights into how the AHR pathway exacerbates bladder cancer response to ICI treatment, which
will provide new opportunities for future drug discovery and precision medicine efforts to minimize HP-irAE in
ICI-treated patients.
Terms: <2,3,7,8-Tetrachlorodibenzo-p-dioxin Receptors><AH Receptors><AHRR><Acceleration><Adverse Experience><Adverse event><Advisory Committees><Aryl Hydrocarbon Receptor><B7-H1><B7H1><Basic Research><Basic Science><Binding><Bladder><Bladder Cancer><Bladder Neoplasm><Bladder Tumors><Bladder Urinary System><CD274><CITE sequencing><CITE-seq><CITEseq><CP11><CY11><CYP1A1><CYP1A1 gene><Cancer Biology><Cancer Causing Agents><Cancer Patient><Cancer Treatment><Cancers><Carcinogens><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Indexing of Transcriptomes and Epitopes by Sequencing><Cessation of life><Checkpoint inhibitor><Clinical><Clinical Trials><Data><Death><Dependence><Detection><Deterioration><Dioxin Receptors><Disease><Disorder><Dreams><Drug Screening><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Equilibrium><Evolution><Fatty Acids><Future><Gene Transcription><Genetic><Genetic Screening><Genetic Transcription><Goals><Grant><Heterogeneity><Heterograft><Heterologous Transplantation><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune Evasion><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune checkpoint inhibitor><Immunes><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunology><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Intermediary Metabolism><Intracellular Communication and Signaling><Label><Ligands><Malignant Bladder Neoplasm><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Bladder><Malignant neoplasm of urinary bladder><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Methods><Mice><Mice Mammals><Modeling><Molecular><Molecular Interaction><Murine><Mus><Nuclear Translocator><Oncogenesis><Oncogenic><Oncogens><P1-450><P450-C><P450DX><P450D\X><PD-L1><PD-L1 therapy><PD-L1 treatment><PDL-1><PDL1><PDL1 therapy><PDL1 treatment><Pathway interactions><Patients><Pattern><Peripheral><Phase><Polyaromatic Hydrocarbon Receptors><Position><Positioning Attribute><Process><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Progressive Disease><Proliferating><Proteomics><RNA Expression><Receptor Activation><Research><Resistance><Role><Sampling><Shapes><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Single cell seq><Solid><Source><Subgroup><TCDD Receptors><Task Forces><Testing><Therapeutic><Training><Transcript><Transcription><Transcription Activation><Transcriptional Activation><Translational Research><Translational Science><Treatment Efficacy><Urinary Bladder Cancer><Urinary Bladder Malignant Tumor><Urinary Bladder Neoplasm><Urinary Bladder Tumor><Work><Xenobiotic Metabolism><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><aPD-L1 therapy><aPD-L1 treatment><advisory team><ahr ligand><anti programmed cell death ligand 1 therapy><anti programmed cell death ligand 1 treatment><anti programmed cell death protein ligand 1 therapy><anti programmed cell death protein ligand 1 treatment><anti-PD-L1 therapy><anti-PD-L1 treatment><anti-PDL1 therapy><anti-PDL1 treatment><anti-cancer therapy><aryl hydrocarbon receptor ligand><balance><balance function><biological signal transduction><cancer cell><cancer cell metabolism><cancer metabolism><cancer microenvironment><cancer progression><cancer therapy><cancer type><cancer-directed therapy><career><cell type><cellular indexing of transcriptomes and epitopes by single cell sequencing><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><drug discovery><epigenetically><exhaust><experiment><experimental research><experimental study><experiments><high dimensional data><immune check point><immune check point inhibitor><immune check point therapy><immune checkpoint><immune checkpoint therapy><immune evasive><immune suppression><immune suppressive activity><immune suppressive function><immune-mediated adverse events><immune-related adverse effect><immune-related adverse events><immune-related adverse reaction><immunecheckpoint><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in vivo><in vivo Model><insight><intervention efficacy><malignancy><metabolism measurement><metabolomics><metabonomics><mouse model><multi-modality><multidimensional data><multidimensional datasets><multidisciplinary><multimodality><murine model><nano-string><nanostring><neoplasm progression><neoplasm/cancer><neoplastic progression><oncogenic agent><overexpress><overexpression><pathway><patient population><precision medicine><precision-based medicine><prevent><preventing><prognostic indicator><programmed cell death ligand 1><programmed cell death protein ligand 1><programs><protein death-ligand 1><protein expression><recruit><resistant><response><response to therapy><response to treatment><single cell next generation sequencing><single cell sequencing><single cell technology><skills><social role><therapeutic efficacy><therapeutic response><therapy efficacy><therapy response><translation research><translational investigation><treatment response><treatment responsiveness><tumor><tumor cell metabolism><tumor growth><tumor metabolism><tumor microenvironment><tumor progression><tumorigenesis><urinary bladder><xeno-transplant><xeno-transplantation><xenograft transplant model><xenotransplant model><αPD-L1 therapy><αPD-L1 treatment>