Immune Tolerance

A major paradigm in cancer immunotherapy is the use of checkpoint inhibitors to break regulatory mechanisms that usually guard the host against autoimmune diseases. CTLA-4-targeting immunotherapy was the first example that helped establish this paradigm. However, the clinically tested anti-CTLA-4 antibodies exhibit suboptimal efficacy but high toxicity. Recent studies have demonstrated that immunotherapy-related adverse events (irAE) and the cancer immunotherapeutic effect (CITE) represent distinct and therapeutically separable activities of anti-CTLA-4 antibodies. The former is attributable to inactivation of the CTLA-4 checkpoint, while the latter is due to selective depletion of regulatory T cells (Treg) in a tumor microenvironment. Here we argue that for safer and more effective CTLA-4-targeting immune therapy, one should preserve rather than inhibit the CTLA-4 checkpoint while enhancing the efficacy and selectivity of Treg depletion in a tumor microenvironment.

The immune system defends the host against infections and malignancies. These mighty tasks are carried out by leukocytes that recognize pathogens and cancer cells through either pattern-recognition receptors (innate immunity) or clonally distributed antigen receptors including B cell surface immunoglobulin and T cell receptors (adaptive immunity). Ligand recognition by these receptors triggers complicated cascades of cellular and molecular interactions that not only numerically increase the number of leukocytes (expansion), but also qualitatively change the properties of the cells (activation and differentiation). Given the brutal force of immune response, multiple layers of regulatory mechanisms are necessary to ensure the immune response is normally controlled to avoid self-destruction.

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Immunotherapy: Open Access