Cytotoxic T lymphocyte antigen - 4 and immune checkpoint blockade

Introduction The immune system is an important defense against the development and progression of cancer (1). Historically, there has been a waxing and waning enthusiasm for immune therapies to treat cancer due to limited efficacy. Immunotherapies, such as IL-2 and adoptive transfer of autologous tumor-infiltrating lymphocytes, can induce durable tumor responses in a subset of patients, leading to long-term survival for patients with an otherwise poor prognosis (2, 3). With improved understanding of the importance for both the priming and effector phases of antitumor immunity, checkpoint blockade-based therapeutics have recently begun providing patients with durable benefits and appear to be applicable in a broad array of malignancies. There are many mechanisms by which tumors evade destruction by the immune system. These mechanisms include recruitment of suppressor immune cells, such as Tregs, myeloid-derived suppressor cells that impair T cell proliferation, and tumorassociated macrophages, which appear to have both tumoricidal and tumorostatic functions. In addition, tumors upregulate programmed death ligand-1 (PD-L1, also known as B7-H1), which binds to the programmed death-1 receptor (PD-1) on the T cell surface to inhibit T cell function (4, 5). Tumors also produce factors associated with immunosuppression, such as TGF-β, IL-10, reactive oxygen species, and nitric oxide (6, 7). Effective antitumor immunity is limited by insufficient costimulation of the immune system by tumor cells (8). These same costimulatory pathways can be involved in priming of the immune system as well as execution of tumor cell killing in the tumor microenvironment. As a result, the targeting of these costimulatory pathways has become a primary area of clinical investigation for cancer therapeutics.