ABSTRACT
PURPOSE OF REVIEW: Immunotherapies have demonstrated robust clinical efficacy in treating malignancies with increasing use and FDA approvals. We review the epidemiology, risk factors, diagnosis, and treatment of immunotherapy-associated cardiovascular toxicities. RECENT FINDINGS: Cardiotoxicity is reported in patients receiving immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cell therapies. The incidence of ICI-related cardiotoxicity is above 1% and includes myocarditis, pericardial disease, arrhythmia, acute coronary syndrome, and vasculitis. The incidence of CAR T cell-associated cardiotoxicities was shown to be as high as 26% and thought to be primarily mediated by cytokine release syndrome. The presentations of cardiotoxicities are variable but are associated with significant morbidity and mortality and benefit from prompt initiation of immunosuppressive therapy. There is increasing evidence for cardiotoxicities following cancer immunotherapy. Available evidence suggests that pretreatment evaluation, close monitoring, and early intervention may reduce cardiovascular morbidity and improve outcomes in the cancer immunotherapy population.
Subject(s)
Neoplasms , Receptors, Chimeric Antigen , Cardiotoxicity/etiology , Cell- and Tissue-Based Therapy , Humans , Immune Checkpoint Inhibitors , Immunotherapy/adverse effects , Neoplasms/drug therapy , Receptors, Chimeric Antigen/therapeutic useABSTRACT
The MST1R (RON) kinase is overexpressed in >80% of human pancreatic cancers, but its role in pancreatic carcinogenesis is unknown. In this study, we examined the relevance of Mst1r kinase to Kras driven pancreatic carcinogenesis using genetically engineered mouse models. In the setting of mutant Kras, Mst1r overexpression increased acinar-ductal metaplasia (ADM), accelerated the progression of pancreatic intraepithelial neoplasia (PanIN), and resulted in the accumulation of (mannose receptor C type 1) MRC1+, (arginase 1) Arg+ macrophages in the tumor microenvironment. Conversely, absence of a functional Mst1r kinase slowed PanIN initiation, resulted in smaller tumors, prolonged survival and a reduced tumor-associated macrophage content. Mst1r expression was associated with increased production of its ligand Mst1, and in orthotopic models, suppression of Mst1 expression resulted in reduced tumor size, changes in macrophage polarization and enhanced T cell infiltration. This study demonstrates the functional significance of Mst1r during pancreatic cancer initiation and progression. Further, it provides proof of concept that targeting Mst1r can modulate pancreatic cancer growth and the microenvironment. This study provides further rationale for targeting Mst1r as a therapeutic strategy.
Subject(s)
Carcinoma, Pancreatic Ductal/pathology , Epithelial Cells/pathology , Macrophages/pathology , Pancreatic Neoplasms/pathology , Receptor Protein-Tyrosine Kinases/metabolism , Animals , Carcinoma, Pancreatic Ductal/enzymology , Disease Progression , Female , Gene Knockdown Techniques , Humans , Intracellular Signaling Peptides and Proteins , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Pancreatic Neoplasms/enzymology , Proof of Concept Study , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Receptor Protein-Tyrosine Kinases/genetics , Signal Transduction , Tumor MicroenvironmentABSTRACT
The RON tyrosine kinase receptor is under investigation as a novel target in pancreatic cancer. While RON mutations are uncommon, RON isoforms are produced in cancer cells via a variety of mechanisms. In this study we sought to: 1) characterize RON isoform expression in pancreatic cancer, 2) investigate mechanisms that regulate isoform expression, and 3) determine how various isoforms effect gene expression, oncogenic phenotypes and responses to RON directed therapies. We quantified RON transcripts in human pancreatic cancer and found expression levels 2500 fold that of normal pancreas with RON isoform expression comprising nearly 50% of total transcript. RNA seq studies revealed that the short form (sfRON) and P5P6 isoforms which have ligand independent activity, induce markedly different patterns of gene expression than wild type RON. We found that transcription of RON isoforms is regulated by promoter hypermethylation as the DNA demethylating agent 5-aza-2'-deoxycytidine decreased all RON transcripts in a subset of pancreatic cancer cell lines. The viability of sfRON-expressing HPDE cells was reduced by a RON specific small molecule inhibitor, while a therapeutic monoclonal antibody had no demonstrable effects. In summary, RON isoforms may comprise half of total RON transcript in human pancreatic cancer and their expression is regulated at least in part by promoter hypermethylation. RON isoforms activate distinct patterns of gene expression, have transforming activity and differential responses to RON directed therapies. These findings further our understanding of RON biology in pancreatic cancer and have implications for therapeutic strategies to target RON activity.
