Overview

Our group’s interest in cardio-oncology and cardio-immunology came about after we defined new cardiovascular clinical syndromes associated with immune checkpoint inhibitors (ICI) including ICI-associated myocarditis and other complications. We have utilized our expertise as myocyte and mouse biologist to generate several pre-clinical models of ICI-associated myocarditis. These models suggest a fundamental role for immune checkpoints (e.g., CTLA-4 and PD-1) in cardiovascular homeostasis. Using novel single-cell platforms and spatial transcriptomics, we are currently elucidating specific immune populations that cause ICI-myocarditis.

Immune Checkpoints and the Heart

In 2016, our group identified a new clinical syndrome of myotoxicity, including myocarditis, associated with immune checkpoint inhibitors (ICI) (NEJM, PMID 27806233; Lancet, PMID 29536852; Lancet Oncol, PMID 30442497). We have utilized our expertise as myocyte and mouse biologists to generate pre-clinical models of ICI-myocarditis which recapitulate the clinical syndrome (Cancer Discov, PMID 33257470). Using novel single-cell platforms and spatial transcriptomics, we are currently elucidating specific immunologic and antigenic drivers of ICI-myocarditis (Nature, PMID 36385524; Circulation, PMID 37746718). We have also identified novel cardiac protective mechanisms against inflammatory damage (Sci Transl Med, PMID 36322628) that may explain how sex affects susceptibility to inflammatory heart disease. We believe we have uncovered a fundamental and previously unappreciated role for immune checkpoints (e.g., CTLA-4, PD-1, LAG-3) in the heart which may have relevance to other cardiac diseases. Current projects in the lab address and extend this concept.

Novel Diagnostic and Therapeutics for Inflammatory Heart Disease

In 2023, we established the UCSF Myocarditis Center, a leading center for diagnosis and treatment of myocarditis. We have leveraged this clinical program to better understand inflammatory cardiomyopathies. Besides being the first to describe ICI-myocarditis clinically, our group is better understanding the pathophysiology and the role of innate and adaptive immune system in other inflammatory cardiomyopathies – from arrhythmogenic genetic cardiomyopathies to vaccine-associate myocarditis.  We are prospectively collecting samples including blood and heart specimen and are applying novel molecular biology and immunologic techniques to better develop diagnostic and treatment strategies for patients. We are utilizing cutting-edge techniques to identify cell-specific transcriptional programs in various types of myocarditis as well as cardiac allograft vasculopathy, including next-generation sequencing, snRNA-sequencing, TCR immune profiling, and spatial transcriptomics (Circ Res, PMID 33934609).

By identifying immune and cardiac mediators of myocarditis at a molecular level, we have uncovered new therapeutic strategies that we are translating to patient care. Using mouse models, we have shown that CTLA-4 signaling plays a causal role in the development of myocarditis. In the mouse models, abatacept (recombinant CTLA4–Ig) blocks T-cell co-stimulation by binding to CD80/CD86 ligands and significantly attenuates myocarditis in mice (Cancer Discov, 2021, PMID 33257470). We successfully treated the first patient with ICI-myocarditis (NEJM, 2019, PMID 31189043). However, we have found that a combination of Janus kinase (JAK) inhibition and CTLA4-Ig potentiates response. In collaboration with colleagues in France, we have successfully treated a case series of patients with ICI-myocarditis with excellent results (Cancer Discov, 2023, PMID 33257470). Current projects in the Moslehi laboratory will be utilizing genomics and genome engineering technologies to better understand cardiovascular-immune interactions and harness reprogrammed immune cells to treat cardiovascular diseases.

Kinase Signaling

Kinase inhibitors used in oncology have been transformative in cancer treatment but can lead to cardiovascular sequelae. Our group has especially been interested in covalent kinase inhibitors and their cardiovascular effects. For example, ibrutinib is a Bruton tyrosine kinase (BTK) inhibitor, which has treatment for a subset of leukemias and lymphoma. Our group has shown that ibrutinib is associated with atrial fibrillation and other arrhythmia (Haematologica, PMID 28751558; Blood, PMID 28223277; JACC, PMID 31558250). Ibrutinib is a first in class covalent kinase inhibitor, binding a free cysteine near the ATP-binding site. While probably more potent and selective with respect to kinase activity, there is the possibility that non-kinase proteins are being targeted. Using cell-based and animal models, our early data suggest a novel mechanism of signaling in atrial fibrillation. By understanding this better, we hope to modulate this signaling pathway for better arrhythmia drugs. 

HIF, Prolyl Hydroxylases and the Heart

The 2019 Nobel prize in medicine was awarded to scientists who defined the regulation of physiologic hypoxia. This oxygen-sensing machinery involves a transcription factor called hypoxia-inducible factor (HIF). Our laboratory has been interested in the roles that HIF plays in cardiovascular biology (Circulation, PMID 20733101; Cell, PMID 26919427). Conversely, drugs targeting HIF can lead to cardiovascular complications and our lab is studying the mechanisms of these sequelae.