title: At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy.
abstract: Tumors can avoid immune surveillance by stimulating immune inhibitory receptors that function to turn off established immune responses. By blocking the ability of tumors to stimulate inhibitory receptors on T cells, sustained, anti-tumor immune responses can be generated in animals. Thus, therapeutic blockade of immune inhibitory checkpoints provides a potential method to boost anti-tumor immunity. The CTLA-4 and PD-1Rs represent two T cell-inhibitory receptors with independent mechanisms of action. Preclinical investigations revealed that CTLA-4 enforces an activation threshold and attenuates proliferation of tumor-specific T lymphocytes. In contrast, PD-1 functions primarily as a stop signal that limits T cell effector function within a tumor. The unique mechanisms and sites of action of CTLA-4 and PD-1 suggest that although blockade of either has the potential to promote anti-tumor immune responses, combined blockade of both might offer even more potent anti-tumor activity. See related review At the Bedside: CTLA-4 and PD-1 blocking antibodies in cancer immunotherapy.
authors.affiliation: Department of Medicine, Cancer Biology and Genetics Program, and Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Intlekofer
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007167:Immunotherapy; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D060908:CTLA-4 Antigen; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
keywords: PD-L1; coinhibitory; costimulation; costimulatory; inhibitory; ipilimumab; receptor; tumor