Guram and Kim et al. review the multi-level, direct and indirect regulatory mechanisms responsible for peripheral T cell tolerance, including negative regulators of proinflammatory signaling, soluble anti-inflammatory factors, inhibitory surface receptors and ligands, and regulatory cell subsets (e.g. regulatory CD4+, CD8+, and B cells). The authors propose a threshold model for natural immune activation. Tumors co-opt regulatory mechanisms to raise the immune activation threshold, while checkpoint blockade counters T cell exhaustion and lowers the level of stimulation required to induce an effective immune response.
Continued discoveries of negative regulators of inflammatory signaling provide detailed molecular insights into peripheral tolerance and anti-tumor immunity. Accumulating evidence indicates that peripheral tolerance is maintained at multiple levels of immune responses by negative regulators of proinflammatory signaling, soluble anti-inflammatory factors, inhibitory surface receptors & ligands, and regulatory cell subsets. This review provides a global overview of these regulatory machineries that work in concert to maintain peripheral tolerance at cellular and host levels, focusing on the direct and indirect regulation of T cells. The recent success of checkpoint blockade immunotherapy (CBI) has initiated a dramatic shift in the paradigm of cancer treatment. Unprecedented responses to CBI have highlighted the central role of T cells in both anti-tumor immunity and peripheral tolerance and underscored the importance of T cell exhaustion in cancer. We discuss the therapeutic implications of modulating the negative regulators of T cell function for tumor immunotherapy with an emphasis on inhibitory surface receptors & ligands-central players in T cell exhaustion and targets of checkpoint blockade immunotherapies. We then introduce a Threshold Model for Immune Activation-the concept that these regulatory mechanisms contribute to defining a set threshold of immunogenic (proinflammatory) signaling required to elicit an anti-tumor or autoimmune response. We demonstrate the value of the Threshold Model in understanding clinical responses and immune related adverse events in the context of peripheral tolerance, tumor immunity, and the era of Checkpoint Blockade Immunotherapy.
Author Info: (1) Department of Radiation Medicine and Applied Sciences, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United States. (2) Department of Radi
Author Info: (1) Department of Radiation Medicine and Applied Sciences, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United States. (2) Department of Radiation Medicine and Applied Sciences, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United States. (3) Moores Comprehensive Cancer Center, University of California, San Diego, San Diego, CA, United States. (4) Department of Radiation Medicine and Applied Sciences, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United States. (5) Division of Hematology and Oncology, Center for Personalized Cancer Therapy, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United States. (6) Division of Hematology and Oncology, Center for Personalized Cancer Therapy, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United States. Laboratory of Cellular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States. (7) Moores Comprehensive Cancer Center, University of California, San Diego, San Diego, CA, United States. (8) Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States. (9) Department of Radiation Medicine and Applied Sciences, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United States. Moores Comprehensive Cancer Center, University of California, San Diego, San Diego, CA, United States.
