A Threshold Model for T-Cell Activation in the Era of Checkpoint Blockade Immunotherapy

Abstract

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.

Packed red blood cells inhibit T-cell activation via ROS-dependent signaling pathways

“…Following specific T-cell receptor (TCR) stimulation in lymphoid organs, T-cells can transmigrate into tissues, primarily exerting their immunological functions in the interstitium. Numerous checkpoints and control mechanisms that interrupt T-cell activation prevent unspecific stimulation and harmful consequences such as autoimmune disease ( 1 ). Among numerous other factors, the quantity and quality of T-cell activation depends on the metabolic micromilieu ( i.e.…”

The epigenetic immunomodulator, HBI-8000, enhances the response and reverses resistance to checkpoint inhibitors

“…The ability of HBI-8000 to enable the immune system to target resistant cancer cells may be due in part to its putative effect on antigen presentation and clonal repopulation of the immune response, or its ability to enhance the reinvigoration of exhausted T cells, or both. Ultimately, HBI-8000 and other class I-selective HDACi may epigenetically alter regulatory mechanisms that contribute to achieving a threshold of immunogenic (proinflammatory) signaling that is required to elicit an anti-tumor or autoimmune response [ 76 ].…”

Low-Dose Nivolumab in Renal Cell Carcinoma: A Real-World Experience

“…Owing to the normal distribution of nivolumab dosages (by means of the Shapiro-Wilk test [19] and visualization of normal Q-Q plots [20]), we elected the median split method to dichotomize the cohort into LD and HD utilizing the maximum dose per body weight of nivolumab that each patient received [21]. We assumed that if there did exist a dose-per-body weight threshold for efficacy of the ICI, then even a single dose above that threshold might have long-lasting activation of the immune process, resulting in antitumor and autoimmune effects [22].…”