Document text
Principal Investigator: Camille Jaime
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $48,974
Funding agency: National Heart Lung and Blood Institute
Immune checkpoint inhibitors (ICIs) have transformed cancer immunotherapy. ICIs optimize T
cell activation and recognition to kill tumor cells. However, ICI treatments may also activate self-
reactive immune cells. Cancer patients may then experience immune-related adverse events
(irAEs), which can target the heart. Cardiac irAEs, like ICI-myocarditis, have low incidence but the
highest mortality rate of all irAEs. Considering that ICI-treatments are suitable for 40% of cancer
patients, ICI-myocarditis presents a significant public health risk. In our preliminary studies, we
found that 1) PD-1 blockade caused myocarditis in 20% of mice, 2) PD-1 KO mice with myocarditis
show high expression of T-cell immunoreceptor with Ig & ITIM domains (TIGIT) on T cells, 3)
Other types of myocarditis like experimental autoimmune myocarditis (EAM) and Coxsackievirus
B3 (CVB3) induced myocarditis also had high TIGIT+ T cells, 4) Regulatory T cells (Tregs) are the
main expressors of TIGIT in myocarditis, and 5) Stimulation of TIGIT shielded the heart from
myocarditis. In this project, we propose the PD-1/PD-L1 pathway together with TIGIT are
essential for peripheral tolerance in protecting the heart from myocarditis. In Aim 1, we will study
the role of TIGIT in ICI-myocarditis. We theorize that the loss of TIGIT signaling combined with
PD-1 blockade will break the peripheral tolerance that protects the heart and worsen ICI-
myocarditis severity. We will administrate a co-blockade of a blocking αTIGIT mAb with a blocking
αPD-1 mAb (Subaim 1.1). We will examine TIGIT-expressing Tregs as the main protectors
against ICI-myocarditis by treating TIGITfl/fl FoxP3cre mice with an αPD-1 blockade mAb (Subaim
1.2). In Aim 2, we will inspect the therapeutic potential of TIGIT for ICI-myocarditis. We
hypothesize that upregulating TIGIT signaling will prevent and treat ICI-myocarditis. First, we will
use an agonistic αTIGIT mAb and see its effect in treating and improving ICI-myocarditis disease
(Subaim 2.1). Then we will test the overexpression of TIGIT in Tregs in preventing ICI-myocarditis
by using viral vector delivery of TIGITfl-stop-fl plamid into FoxP3cre mice (Subaim 2.2). Our results
may help elucidate a novel therapeutic target for ICI-induced myocarditis by using the TIGIT
pathway. This would greatly help cancer patients who suffer from this devastating adverse effect
because of their cancer treatment. Since TIGIT is expressed in other kinds of myocarditis, we can
also explore this therapy in other inflammatory cardiovascular conditions.
Terms: <AAV vector><AAV-based vector><Ablation><Abscission><Adverse effects><Antibodies><Autoimmune cardiomyopathy><Autoimmune myocarditis><Autoimmune-mediated myocarditis><Autoregulation><CD152><CD152 Antigen><CD152 Gene><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CRE Recombinase><CTLA 4><CTLA-4 Gene><CTLA4><CTLA4 gene><CTLA4-TM><Cancer Patient><Cancer Treatment><Cancers><Cardiac><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Checkpoint inhibitor><Clinical Treatment Moab><Coxsackie Viruses><Coxsackievirus><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><Cytotoxic cell><Data><Death><Death Rate><Disease><Disorder><Eligibility><Eligibility Determination><Enterobacteria phage P1 Cre recombinase><Excision><Extirpation><FOXP3><FOXP3 gene><Forkhead Box P3><Goals><Heart><Heart Vascular><Homeostasis><ITIM><Immune><Immune Globulins><Immune checkpoint inhibitor><Immune infiltrates><Immune mediated therapy><Immunes><Immunoglobulins><Immunologically Directed Therapy><Immunoreceptor Tyrosine-Based Inhibitory Motif><Immunotherapy><Incidence><Inflammation><Inflammatory><Intracellular Communication and Signaling><JM2><K lymphocyte><KO mice><Knock-out Mice><Knockout Mice><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Measures><Mediating><Mice><Mice Mammals><Monoclonal Antibodies><Murine><Mus><Myocarditis><NK Cells><Natural Killer Cells><Newly Diagnosed><Null Mouse><Oncology><Oncology Cancer><PD-L1 pathway><PDL1 pathway><Pathway interactions><Patients><Peripheral><Physiological Homeostasis><Plasmids><Preventative measure><Prevention><Preventive measure><Protocol Screening><Public Health><Receptor Protein><Regulatory T-Lymphocyte><Removal><Reporting><Research><Risk><Role><SCURFIN><Self Tolerance><Severities><Severity of illness><Signal Transduction><Signal Transduction Systems><Signaling><Surface><Surgical Removal><T cell regulation><T-Cell Activation><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T4 Cells><T4 Lymphocytes><Testing><Therapeutic><Treatment Protocols><Treatment Regimen><Treatment Schedule><Treg><Tumor Cell><Up-Regulation><Upregulation><Viral Vector><aPD-1><aPD1><activate T cells><adeno-associated viral vector><adeno-associated virus vector><anti programmed cell death 1><anti-PD-1><anti-PD1><anti-cancer immunotherapy><anti-cancer therapy><anti-programmed cell death protein 1><antiPD-1><antiPD1><anticancer immunotherapy><antigen-specific T cells><autoimmune reactivity><autoreactive T cell><autoreactivity><bacteriophage P1 recombinase Cre><biological signal transduction><cancer cell><cancer clinical trial><cancer immunotherapy><cancer therapy><cancer-directed therapy><cardiac inflammation><circulatory system><cytotoxic T-lymphocyte antigen 4><delivery vector><delivery vehicle><disease severity><experience><immune cell infiltrate><immune check point><immune check point inhibitor><immune checkpoint><immune modulatory intervention><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-related adverse effect><immune-related adverse events><immune-related adverse reaction><immunecheckpoint><immuno therapy><immunointervention><immunological intervention><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><mAbs><malignancy><member><monoclonal Abs><mortality rate><mortality ratio><neoplasm/cancer><neoplastic cell><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><oncology clinical trial><overexpress><overexpression><pathway><peripheral tolerance><prevent><preventing><programmed cell death ligand 1 pathway><programmed cell death protein ligand 1 pathway><programs><promoter><promotor><receptor><regulatory T-cells><resection><response><self-reactive T cell><social role><theories><thymus derived lymphocyte><tumor><αPD-1><αPD1>