Search

The specific BCL-2 small molecule inhibitor venetoclax has been shown to effectively induce apoptosis in a wide range of malignancies either alone and in combination with other drugs. Based upon these results, there has been considerable growth in its use in clinical studies used alone and in combination with chemotherapy and immune-based therapies. Lympho- cytes, and T cells in particular, rely heavily on BCL-2 for survival and function. This has been determined largely by genetic deletion or overexpression of BCL-2 in murine models. However, the adaptive effects of short or long-term small molecule BCL-2 family blockade on surviving immune cell subsets and their function is not fully understood. In the current work, we aimed to better understand the effect of long-term systemic treatment with venetoclax on regulatory T (Treg) cells, which are relatively apoptotically resistant to specific BCL-2 drugging compared to other T cells. Our results indicate that long-term BCL-2 blockade by venetoclax results in Treg plasticity towards a TH17-like functional state which aids in anti-PD-1 efficacy. Our data further highlights the importance of Treg instability on the efficacy of anti-PD-1 checkpoint blockade which will be beneficial for the clinical efficacy of immunotherapy.

Coronary chronic total occlusion (CTO) contributes to the progression of heart failure in patients with ischemic cardiomyopathy. Randomized controlled trials demonstrated that percutaneous coronary intervention (PCI) for CTO significantly improves angina symptoms and quality of life but fails to reduce clinical events compared with optimal medical therapy. Even so, intervening physicians strongly support CTO-PCI. Cardiac regeneration therapy after CTO-PCI should be a promising approach to improving the prognosis of ischemic cardiomyopathy. However, the relationship between CTO revascularization and cardiac regeneration has rarely been studied, and experimental studies on cardiac regeneration usually employ rodent models with permanent ligation of the coronary artery rather than reopening of the occlusive artery. Limited early-stage clinical trials demonstrated that cell therapy for cardiac regeneration in ischemic cardiomyopathy reduces scar size, reverses cardiac remodeling, and promotes angiogenesis. This review focuses on the status quo of CTO-PCI in ischemic cardiomyopathy and the clinical prospect of cardiac regeneration in this setting.