Cancer immunotherapy by targeting immune checkpoint receptors

Abstract

The immune system plays a pivotal role in defending our body from invading pathogens and in surveillance against cancer. While most cells that acquire mutations are detected and destroyed by immunocytes, a small number of transformed cells succeed in evading immune destruction by inhibiting immune checkpoint regulatory pathways, leading to suppression of anti-cancer immune responses. Under normal conditions, immune checkpoint receptors maintain self-tolerance, prevent immunopathology, and regulate overall immune homeostasis. However, their skewed activation by cancer cells may lead to the suppression of nascent anti-tumor immunity and the promotion of tumor growth. Discovering the role of immune checkpoints in cancer and understanding their mode of operation has led to the development of novel strategies for cancer immunotherapy, which are based on the intervention or blockade of immune checkpoint-regulated pathways. Clinical studies have demonstrated that immune checkpoint co-inhibitory receptor-blocking antibodies can revert tumor-induced immunosuppression and augment overall anti-tumor immunity. These antibodies induced durable clinical responses and unprecedented therapeutic benefits in multiple types of malignancies. Although immune checkpoint inhibitors have revolutionized cancer therapy, the clinical benefits of these drugs have been limited to subsets of cancer patients and treatments frequently associated with a unique spectrum of toxicities, termed immune-related adverse events. Future discoveries of novel immune checkpoint receptors, identification of new prognostic and predictive biomarkers, and improvement of combination therapies are likely to boost the success rate of cancer immunotherapy and increase the survival rates of patients with different types of cancers.

Keywords: Immune checkpoint; Immunotherapy; Cancer; Autoimmune diseases; T lymphocytes

Core tip: The major functions of immune checkpoint receptors are to maintain self-tolerance, prevent immunopathology, and regulate overall immune homeostasis. However, skewed activation of these receptors by cancer cells may lead to suppression of nascent anti-tumor immunity and promote tumor cell growth. Clinical studies have demonstrated that blocking inhibitory immune checkpoint receptors induced durable clinical responses and unprecedented therapeutic benefits in multiple types of malignancies. The present editorial addresses some of the major immune checkpoint receptor targets in cancer immunotherapy, discusses some of the side effects and limitations in their utilization, and highlights some of the future challenges in the field.