Mechanism of T cell exhaustion in a chronic environment

Clinically feasible approaches to potentiating cancer cell-based immunotherapies

“…Recent reports showed that in addition to CTLA-4 and PD-1, other inhibitory receptors, such as lymphocyte activation gene 3 (LAG-3), T cell immunoglobulin mucin 3 (TIM-3), natural killer cell receptor 2B4 (2B4, CD244), leukocyte immunoglobulin-like receptor superfamily B member 3 (LILRB3, PIRB) and 4 (LILRB4, GP49), and CD160, are co-expressed on exhausted T cells during tumor progression. 21 Some tumors are known to overexpress ligands for the receptors mentioned above, thus contributing to local immunosuppression. In addition, soluble immunosuppressive factors present in the tumor microenvironment could also support functional inhibition of exhausted T cells.…”

“…TGF-b controls immune responses and maintains immune homeostasis by affecting proliferation, differentiation, and survival of multiple immune cell lineages. 21 IL-10 has been shown to reduce proinflammatory cytokine production, impede APC function, dampen T cell responses, and also affect B cell dysregulation. 21 Vascular endothelial growth factor (VEGF) is another cytokine that exerts a negative effect on the development of tumor-specific T-cell responses; specifically, it contributes to tumor immune escape by inducing immunosuppressive cells.…”

“…21 IL-10 has been shown to reduce proinflammatory cytokine production, impede APC function, dampen T cell responses, and also affect B cell dysregulation. 21 Vascular endothelial growth factor (VEGF) is another cytokine that exerts a negative effect on the development of tumor-specific T-cell responses; specifically, it contributes to tumor immune escape by inducing immunosuppressive cells. 23 VEGF is known to stimulate tumor angiogenesis and vasculogenesis to support blood supply to the growing tumor.…”

“…Indirect suppression may also occur via production of immunosuppressive cytokines, such as IL-10 or TGF-b. 21 Regulatory B cells (Bregs) secrete IL-10 and TGF-b shifting the balance of tumor-specific immune responses toward immunosuppression, thus sustaining tumor progression. 15 A Th1/Th2 imbalance is often established during tumor development, with the predominance of anti-inflammatory (Th2) cytokines.…”

“…24 Importantly, these mediators are produced not only by tumor cells, but also by non-malignant stromal cells. 21 Immunosuppressive enzymes A variety of tumors are characterized by elevated expression of the immunosuppressive tryptophan converting enzyme indoleamine-2,3-dioxygenase (IDO). In normal physiology, IDO metabolizes tryptophan and limits T-and NK-cell activation in local tissue microenvironments, such as the placenta.…”