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Principal Investigator: Arabella Young
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2024
Award: $249,000
Funding agency: National Cancer Institute
Project Summary/Abstract
Tumors elicit a range of suppressive mechanisms in order to evade the immune system. Many of these are
targetable as evidenced by the great success of cancer immunotherapies that boost a patient's own immune
response towards cancer. Often, targets for cancer immunotherapies represent pathways that at homeostasis
protect against activation of an immune response towards self, limiting the development of autoimmune
disease. Cancer patients treated with immune-potentiating therapies are exposed to significant risk of
developing immune-related adverse events (irAEs). These irAEs have been reported in nearly every organ
system, and in many cases represent non-resolving autoimmune side-effects that pose a significant impact
due to their potential morbidity, mortality and associated healthcare costs. With a growing number of
immunotherapies reaching clinical utility and increasing combination studies that may initiate more frequent
and severe irAEs, understanding which therapeutic approaches provide improved tumor control with minimal
side-effects is essential. In this study, by generating transplantable, syngeneic tumor cell lines in autoimmune-
prone NOD mice, which develop autoimmune pathologies in response to cancer immunotherapies, we may
begin to assess the interplay between irAEs and anti-tumor immunity. In-depth profiling of genetic, epigenetic
and cellular mechanisms that separate anti-tumor immunity versus autoimmunity in response to cancer
immunotherapies will be defined to better engineer therapeutic strategies that enhance the immune response
towards tumor with limited impact towards self. Using NOD tumors resistant to clinically-approved cancer
immunotherapies such as anti-PD-1 and anti-CTLA-4, combination therapeutic strategies that reinvigorate
immune activation in the tumor microenvironment will be identified and the associated risk for precipitating
irAEs determined. Together, these preclinical models provide a platform to assess safety profiles for cancer
immunotherapies, identifying mechanisms to inhibit or avoid irAEs while preserving anti-tumor immunity. This
research will be performed amongst world-class scientists and facilities at the University of California, San
Francisco, this environment will foster expert training in the analysis of high-dimensional datasets generated
from CyTOF and 10X single-cell RNA and TCR sequencing, an essential skill for delineating the complex
mechanisms contributing to immune-mediated disease. Both my mentorship committee, led by Dr. Jeffrey
Bluestone and expert collaborators will allow me to fulfil these research goals. Following, I will transition to an
independent position establishing a research program that integrates the effect of multiple environmental
factors, including microbiome, diet, age and stress, alongside autoimmune and anti-tumor immune responses
to cancer immunotherapy using the NOD tumor models that have been developed, with the ultimate aim to
improve safety, specificity and treatment efficacy for immunotherapy-treated cancer patients.
Terms: <Age><Autoimmune><Autoimmune Diseases><Autoimmune Status><Autoimmunity><Autoregulation><Body System><Body Tissues><Brittle Diabetes Mellitus><California><Cancer Patient><Cancer Treatment><Cancers><Causality><Cellular Immune Function><Circadian Rhythms><Clinical><Combined Modality Therapy><Complex><Data Set><Development><Diet><Disease><Disorder><Ecological impact><Engineering><Environment><Environmental Factor><Environmental Impact><Environmental Risk Factor><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Etiology><Event><Exposure to><Follow-Up Studies><Followup Studies><Fostering><Frequencies><Genetic><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic propensity><Goals><Health Care Costs><Health Costs><Healthcare Costs><Homeostasis><IDDM><Immune><Immune Cell Activation><Immune Evasion><Immune Modulation Therapy><Immune Precipitation><Immune infiltrates><Immune mediated therapy><Immune response><Immune system><Immunes><Immunity><Immunological response><Immunologically Directed Therapy><Immunoprecipitation><Immunotherapy><Inbred NOD Mice><Inherited Predisposition><Inherited Susceptibility><Insulin-Dependent Diabetes Mellitus><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Mentorship><Mice><Mice Mammals><Modality><Modeling><Molecular><Morbidity><Morbidity - disease rate><Mouse Strains><Multimodal Therapy><Multimodal Treatment><Murine><Mus><NOD Mouse><Neoplasm Transplantation><Non obese><Non-Obese Diabetic Mice><Nonobese><Nonobese Diabetic Mouse><Nyctohemeral Rhythm><Organ System><PD 1><PD-1><PD1><Pathology><Pathway interactions><Patients><Phase><Physiological Homeostasis><Position><Positioning Attribute><Pre-Clinical Model><Preclinical Models><Predisposition gene><Regimen><Reporting><Research><Resistance><Risk><Role><Safety><San Francisco><Scientist><Self Tolerance><Severities><Specificity><Stress><Sudden-Onset Diabetes Mellitus><Susceptibility Gene><T cell receptor repertoire sequencing><T cell receptor sequencing><T1 DM><T1 diabetes><T1D><T1DM><TCR repertoire sequencing><TCR sequencing><TCR-seq><TCRseq><Therapeutic><Tissues><Training><Transplantation><Treatment Efficacy><Tumor Cell Line><Tumor Immunity><Twenty-Four Hour Rhythm><Type 1 Diabetes Mellitus><Type 1 diabetes><Type I Diabetes Mellitus><Universities><aCTLA-4><aCTLA4><ages><anti-CTLA-4><anti-CTLA4><anti-cancer immunotherapy><anti-cancer therapy><anti-tumor immune response><anti-tumor immunity><anticancer immunotherapy><antitumor immunity><autoimmune condition><autoimmune disorder><autoimmunity disease><cancer care><cancer immunity><cancer immunotherapy><cancer microenvironment><cancer therapy><cancer type><cancer-directed therapy><causation><circadian process><combination therapy><combinatorial><combined modality treatment><combined treatment><daily biorhythm><design><designing><developmental><diabetic><diets><dimensional analysis><disease causation><environmental risk><epigenetically><genetic etiology><genetic mechanism of disease><genetic profiling><genetic vulnerability><genetically predisposed><high dimensional data><high dimensionality><host response><immune activation><immune cell infiltrate><immune check point><immune checkpoint><immune evasive><immune function><immune microenvironment><immune modulating therapies><immune modulatory therapies><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immune-mediated adverse events><immune-modulation treatment><immune-related adverse effect><immune-related adverse events><immune-related adverse reaction><immunecheckpoint><immuno therapy><immunomodulation therapy><immunomodulation treatment><immunomodulator therapies><immunomodulator treatment><immunomodulator-based therapies><immunomodulatory therapies><immunomodulatory therapy><immunomodulatory treatment><immunoresponse><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><immunotherapy for cancer><immunotherapy of cancer><immunotoxicity><improved><insight><insulin dependent diabetes><insulin dependent type 1><intervention efficacy><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><malignancy><microbiome><mortality><mouse model><multi-modal therapy><multi-modal treatment><multidimensional data><multidimensional datasets><murine model><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non-obese diabetic (NOD) mice><nonobese diabetic (NOD) mice><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathway><pre-clinical><pre-clinical development><preclinical><preclinical development><predisposing gene><preservation><prevent><preventing><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><resistance mechanism><resistant><resistant mechanism><response><safety assessment><scRNA-seq><side effect><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><skills><sle2><social role><success><survival outcome><susceptibility allele><susceptibility locus><susceptibility variant><systemic lupus erythematosus susceptibility 2><therapeutic efficacy><therapy efficacy><toxic reaction in immunology><transplant><treatment strategy><tumor><tumor immune microenvironment><tumor microenvironment><tumor transplant><tumor transplantation><tumor-immune system interactions><type I diabetes><type one diabetes><α-CTLA-4><α-CTLA4><αCTLA-4><αCTLA4>