Abstract P3074: Immune Checkpoint Inhibition Reshapes Cardiac Immune Landscape Through Crosstalk Between Macrophage And T-cell

Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein 1(PD-1)/ programmed death-ligand 1(PD-L1) have revolutionized cancer management since the approval. However, they are associated with immune-related adverse events (irAEs), including myocarditis. ICI-associated myocarditis is often fulminant and fatal. The associated major risk factor is the combination of CTLA-4 and PD-1 inhibition. The mechanistic basis of ICI-associated myocarditis is unclear and mechanism-based treatment strategies are needed. Crosstalk between T-cells and macrophages may represent one pathogenic mechanism underlying ICI-associated myocarditis. We employed an established mouse model Ctla4 +/- Pdcd1 -/- to study the crosstalk between T-cells and macrophage in the heart and its impact on reshaping cardiac immune landscape using unbiased single cell-RNA-seq technology. We discovered a more inflammatory cardiac microenvironment in ICI-associated myocarditis mouse, characterized by CD68 + cells infiltration, robust CCR2 signal, enhanced T-cells activation with interferon gamma (IFN-γ) secretion and increased frequency of Cxcl9 + Cxcl10 + macrophages with an activated phenotype enriched in response to IFN-γ. Importantly, the existence of Cxcl9 + Cxcl10 + macrophages (characterized by CD16α and CXCL9/CXCL10 expression) was confirmed in human ICI-associated myocarditis specimens which establishes a connection between mouse model and human disease. Analysis of cell communication between myeloid cells and T-cells predicted that Cxcl9 + Cxcl10 + macrophages communicate with T-cells via IFN-γ-IFN-γR and Cxcl9/Cxcl10-CXCR3 signals. Pseudotime time analysis suggests Cxcl9 + Cxcl10 + macrophages were derived from monocytes. Blocking IFN-γ signal prolonged the survival time of ICI-associated myocarditis mouse and reduced emergence of Cxcl9 + Cxcl10 + macrophages in the heart suggesting specific blocking the mediator of crosstalk between T-cells and macrophages attenuated ICI-associated myocarditis. This study will provide support to the usage of IFN-γ as a potential target to prevent ICI associated myocarditis during or at the end of ICI therapy in cancer patients.