Only after their introduction into clinical trials did irAEs become evident and it became clear that reverse translational animal models are desperately needed. A study looking at efficacy of anti-PD-1 therapy in combination with anti-tumor necrosis factor (TNF) therapy to enhance antitumor efficacy was published suggesting that this combination could achieve a synergistic effect.26 More recently, a manuscript highlighted the possibility of uncoupling irAEs from ICI treatment effects in a mouse model.27 In their study, the authors treated mice with dextran sodium sulfate (DSS) to chemically induce colitis in mice with tumor. associated with risk for myocarditis. They identified that female patients and patients over the age of 75 were at greatest PFK-158 risk for myocarditis.24 In a review of WHO database of immunotherapy-associated myocarditis, mortality was reported to be 67% for patients who received combination therapy and 36% with anti-PD-(L)1 targeting antibodies.25 The current hypotheses regarding the development of cardiac toxicity relate to T cell-mediated infiltration of cardiac tissue in response to cross-reactive antigens. A postmortem analysis from one patient revealed shared clonality of T cell receptors (TCR) in tumor-infiltrating T cells and cardiac-infiltrating T cells without evidence of antibody involvement.23 Overall, irAEs are a heterogeneous group of immune-mediated phenomena affecting multiple organ systems. Surprisingly, animal models testing checkpoint inhibitors showed adequate anticancer benefit, without evidence of toxicity. Only after their introduction into clinical trials did irAEs become evident and it became clear that reverse translational animal models are desperately needed. A study looking at efficacy of anti-PD-1 therapy in combination with anti-tumor necrosis factor (TNF) therapy to enhance antitumor efficacy was published suggesting that this combination could achieve a synergistic effect.26 More recently, a manuscript highlighted the possibility of uncoupling irAEs from ICI treatment effects in a mouse model.27 In their study, the authors treated mice with dextran sodium sulfate (DSS) to chemically induce colitis in mice with tumor. Further, mice were given with combination immunotherapy (anti-PD-1 and anti-CTLA-4) as well as anti-TNF alpha antibody. The data suggested that tumor shrank and colitis improved. The authors concluded that this may be an effective strategy to uncouple toxicity from efficacy. While this study is interesting and can shed some light on basic biology, there are some major caveats. DSS colitis is a chemically mediated disease; it is known to respond well to anti-TNF therapy and animals treated with ICIs do not recapitulate human toxicity. Indeed, better reverse translational models are needed to study irAEs in PFK-158 animals. In patients suffering from gastrointestinal irAEs, anti-TNF therapy has been used. In this recent report, five patients were treated with concomitant infliximab and immunotherapy regimen with resolution of gastrointestinal complications and no evidence of malignancy progression.28 Data have supported the hypothesis that irAE development is associated with increased progression-free survival (PFS) and overall RHOC survival (OS) in a variety of tumor types, especially NSCLC, suggesting shared mechanisms for antitumor effects and irAE development.29C33 As our understanding of irAEs with ICIs deepens, we will likely be able to develop more targeted therapies to prevent toxicity while maintaining enhanced antitumor responses. T cells in irAE pathogenesis With the emergence of irAEs, a new field to study their pathogenesis has emerged. To date, the most likely culprit of disease initiation and progression is the T cell. Several translational studies have shed light on the importance of new specific T cell clones, which can lead to toxicity. In one manuscript, authors Johnson profiled infiltrating immune cells from a patient who developed encephalitis after treatment with pembrolizumab. Interestingly, the areas of inflammation had increased numbers of T cells with memory phenotypes. In addition, they found three predominant T cell clones recognizing Epstein-Barr virus (EBV) viral proteins with some matching known HLA-A2-restricted EBV-specific TCRs and cytotoxic CD4+ T?cell clones with high PD-L1 staining.34 In a similar study evaluating the etiology of fatal ICI-induced myocarditis, Johnson describe clonal infiltrating T cell populations in common between the tumor and myocardium.23 Cardiac histology revealed infiltration of CD3+ T cells PFK-158 and patchy PFK-158 necrosis of myofibrils. The authors hypothesized that there was a shared epitope between the target malignant cells and bystander cardiac myofibrils. A third study evaluating the pathophysiology of checkpoint-induced pneumonitis (CIP) compared the composition of bronchoalveolar lavage fluid in ICI patients with CIP versus those who were treated with ICI and did not develop CIP. Using multiparameter flow cytometry, the investigators found that bronchoalveolar lymphocytosis could serve as a hallmark for CIP. Specifically, they found increased CD8+ T cells as well as central memory T cells, decreased numbers of regulatory T cells and higher numbers of activated macrophages in their bronchoalveolar lavage fluid.35 Oh hypothesized that IPI would lead to an expansion of tissue-specific T cell clones, driving irAE development. Instead of an expansion of subclinical tissue-specific PFK-158 clones, they saw an increase in de novo.