Immune checkpoints are accessory molecules that either promote or inhibit T cell activation. Two inhibitory molecules, cytotoxic T cell antigen 4 (CTLA-4) and programmed death 1 (PD-1), got high attention, as inhibition of CTLA-4 or PD-1 signaling provides the first immune therapy that significantly improves the survival of patients with metastatic solid cancers. Inhibition of CTLA-4 or PD-1 was first studied in and approved for patients with metastatic melanoma. Blocking immune checkpoints is also efficient in non-small-cell lung cancer, renal cell cancers, hypermutated gastro-intestinal cancers and others. Immune responses, whether directed against infections or against tumors, are divided into two phases: an initiation and activation phase, where the immune system recognizes a danger signal and becomes activated by innate signals to fight the danger. This reaction is fundamental for the control of infections and cancer, but needs to be turned off once the danger is controlled, as persistence of this activation ultimately causes severe tissue damage. Therefore, each activation of the immune system is followed by a termination phase, where endogenous immune suppressor molecules arrest immune responses to prevent harmful damage. In the case of cancer immune therapies, therapeutic approaches classically enhanced the initiation and activation of immune responses to increase the emergence and the efficacy of cytotoxic T cells (CTL) against cancers. In sharp contrast, immune checkpoint blockade focuses on the termination of immune responses by inhibiting immune suppressor molecules. It thus prevents the termination of immune responses or even awakes those CTLs that became exhausted during an immune response. Therefore, blocking negatively regulating immune checkpoints restores the capacity of exhausted CTL to kill the cancer they infiltrate. In addition, they drive surviving cancer cells into a still poorly defined state of dormancy. As the therapy awakes also self-reactive CTL, one downside of the therapy is the induction of organ-specific autoimmune diseases. The second downside is the exorbitant drug price that withdraws patients at need from a therapy that was developed by academic research that impairs further academic treatment development and financially charges the public health system.
The Journal of allergy and clinical immunology. 2018 Mar 26 [Epub ahead of print]
Thomas Wieder, Thomas Eigentler, Ellen Brenner, Dipl Biol, Martin Röcken
Department of Dermatology, Eberhard Karls University, Liebermeisterstr. 25, 72076 Tübingen, Germany., Department of Dermatology, Eberhard Karls University, Liebermeisterstr. 25, 72076 Tübingen, Germany. Electronic address: .