Cardiovascular toxicities associated with immune checkpoint inhibitors (ICIs) have been reported in case series but have been underappreciated due to their recent emergence, difficulties in diagnosis and non-specific clinical manifestations. ICIs are antibodies that block negative regulators of the T cell immune response, including cytotoxic T lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and PD-1 ligand (PD-L1). While ICIs have introduced a significant mortality benefit in several cancer types, the augmented immune response has led to a range of immune-related toxicities, including cardiovascular toxicity. ICI-associated myocarditis often presents with arrhythmias, may co-exist with myositis and myasthenia gravis, can be severe, and portends a poor prognosis. In addition, pericardial disease, vasculitis, including temporal arteritis, and non-inflammatory heart failure, have been recently described as immune-related toxicities from ICI. This narrative review describes the epidemiology, diagnosis, pathophysiology, and treatment of cardiovascular toxicities of ICI therapy, highlighting recent developments in the field in the past year. Keywords Cardio-oncology • Immune checkpoint inhibitors • Myocarditis • Vasculitis • Pericarditis • Cardiovascular toxicity This article is part of the Spotlight Issue on Cardio-oncology.

Rationale: Fibrosis is mediated partly by extracellular matrix–depositing fibroblasts in the heart. Although these mesenchymal cells are reported to have multiple embryonic origins, the functional consequence of this heterogeneity is unknown. Objective: We sought to validate a panel of surface markers to prospectively identify cardiac fibroblasts. We elucidated the developmental origins of cardiac fibroblasts and characterized their corresponding phenotypes. We also determined proliferation rates of each developmental subset of fibroblasts after pressure overload injury. Methods and Results: We showed that Thy1 + CD45 − CD31 − CD11b − Ter119 − cells constitute the majority of cardiac fibroblasts. We characterized these cells using flow cytometry, epifluorescence and confocal microscopy, and transcriptional profiling (using reverse transcription polymerase chain reaction and RNA-seq). We used lineage tracing, transplantation studies, and parabiosis to show that most adult cardiac fibroblasts derive from the epicardium, a minority arises from endothelial cells, and a small fraction from Pax3-expressing cells. We did not detect generation of cardiac fibroblasts by bone marrow or circulating cells. Interestingly, proliferation rates of fibroblast subsets on injury were identical, and the relative abundance of each lineage remained the same after injury. The anatomic distribution of fibroblast lineages also remained unchanged after pressure overload. Furthermore, RNA-seq analysis demonstrated that Tie2-derived and Tbx18-derived fibroblasts within each operation group exhibit similar gene expression profiles. Conclusions: The cellular expansion of cardiac fibroblasts after transaortic constriction surgery was not restricted to any single developmental subset. The parallel proliferation and activation of a heterogeneous population of fibroblasts on pressure overload could suggest that common signaling mechanisms stimulate their pathological response.

A significant risk in the clinical application of human pluripotent stem cells (hPSCs), including human embryonic and induced pluripotent stem cells (hESCs and hiPSCs), is teratoma formation from residual undifferentiated cells. We have raised a monoclonal antibody (mAb) against hESCs, designated SSEA-5, which binds a novel antigen highly and specifically expressed on hPSCs--the H type-1 glycan. Separation of SSEA-5 high cells through fluorescence-activated cell sorting (FACS) drastically reduced teratoma formation potential. To ensure complete removal we identified additional markers exhibiting a large dynamic expression range during differentiation: CD9, CD30, CD50, CD90, and CD200. Immunohistochemistry (IHC) conducted on human fetal tissues and bioinformatics analysis of a microarray database revealed that concurrent expression of these markers is both common and specific to hPSCs. When applied to incompletely differentiated hESC cultures, immunodepletion with SSEA-5 and 2 additional markers completely removed teratoma formation potential.

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