T Cell Based Immunotherapy for Cancer: Approaches and Strategies.

T cells are critical in destroying cancer cells by recognizing antigens presented by MHC molecules on cancer cells or antigen-presenting cells. Identifying and targeting cancer-specific or overexpressed self-antigens is essential for redirecting T cells against tumors, leading to tumor regression. This is achieved through the identification of mutated or overexpressed self-proteins in cancer cells, which guide the recognition of cancer cells by T-cell receptors. There are two main approaches to T cell-based immunotherapy: HLA-restricted and HLA-non-restricted Immunotherapy. Significant progress has been made in T cell-based immunotherapy over the past decade, using naturally occurring or genetically engineered T cells to target cancer antigens in hematological malignancies and solid tumors. However, limited specificity, longevity, and toxicity have limited success rates. This review provides an overview of T cells as a therapeutic tool for cancer, highlighting the advantages and future strategies for developing effective T cell cancer immunotherapy. The challenges associated with identifying T cells and their corresponding antigens, such as their low frequency, are also discussed. The review further examines the current state of T cell-based immunotherapy and potential future strategies, such as the use of combination therapy and the optimization of T cell properties, to overcome current limitations and improve clinical outcomes.

Spleen Tyrosine Kinase phosphorylates VE-cadherin to cause endothelial barrier disruption in acute lung injury.

Increased endothelial cell (EC) permeability is a cardinal feature of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Tyrosine phosphorylation of VE-cadherin is a key determinant of EC barrier disruption. However, the identity and role of tyrosine kinases in this context are incompletely understood. Here we report that Spleen Tyrosine Kinase (Syk) is a key mediator of EC barrier disruption and lung vascular leak in sepsis. Inhibition of Syk by pharmacological or genetic approaches, each reduced thrombin-induced EC permeability. Mechanistically, Syk associates with and phosphorylates VE-cadherin to cause EC permeability. To study the causal role of endothelial Syk in sepsis-induced ALI, we used a remarkably efficient and cost-effective approach based on gene transfer to generate EC-ablated Syk mice. These mice were protected against sepsis-induced loss of VE-cadherin and inflammatory lung injury. Notably, the administration of Syk inhibitor R788 (fostamatinib); currently in phase II clinical trial for the treatment of COVID-19, mitigated lung injury and mortality in mice with sepsis. These data identify Syk as a novel kinase for VE-cadherin and a druggable target against ALI in sepsis.