PD-1/PD-L1 in Cancer: Pathophysiological, Diagnostic and Therapeutic Aspects

Abstract

Immune evasion is a key strategy adopted by tumor cells to escape the immune system while promoting their survival and metastatic spreading. Indeed, several mechanisms have been developed by tumors to inhibit immune responses. PD-1 is a cell surface inhibitory receptor, which plays a major physiological role in the maintenance of peripheral tolerance. In pathological conditions, activation of the PD-1/PD-Ls signaling pathway may block immune cell activation, a mechanism exploited by tumor cells to evade the antitumor immune control. Targeting the PD-1/PD-L1 axis has represented a major breakthrough in cancer treatment. Indeed, the success of PD-1 blockade immunotherapies represents an unprecedented success in the treatment of different cancer types. To improve the therapeutic efficacy, a deeper understanding of the mechanisms regulating PD-1 expression and signaling in the tumor context is required. We provide an overview of the current knowledge of PD-1 expression on both tumor-infiltrating T and NK cells, summarizing the recent evidence on the stimuli regulating its expression. We also highlight perspectives and limitations of the role of PD-L1 expression as a predictive marker, discuss well-established and novel potential approaches to improve patient selection and clinical outcome and summarize current indications for anti-PD1/PD-L1 immunotherapy.

Glucocorticoid and PD-1 Cross-Talk: Does the Immune System Become Confused?

“…PD-L1 is expressed on antigen presenting cells (APCs), including DCs and macrophages, tumor cells, T cells, B cells, and non-lymphoid tissues (pancreatic islet cells, cardiac endothelium). PD-L1 is also expressed in sites of immune privilege, such as the placenta, testes, and eye [33]. In contrast, PD-L2 expression is induced upon macrophage and DC activation [34].…”

“…Increased expression of PD-1 on T cells results in a dampening of T cell activation, thereby avoiding an exaggerated response that could be harmful if directed towards self-antigens. Therefore, any stimulus that induces PD-1 expression on activated T cells protects cancer cells from immune attack [33].…”

“…Indeed, blocking PD-1/PD-L1 has become an important therapeutic approach for several cancers, aimed at enhancing T cell-mediated anti-tumor immunity. The oldest example of a mAb against PD-1 is nivolumab, first used for metastatic melanoma [99] and now demonstrated to be effective in an increasing number of cancers [33,47,100]. However, anti-PD-1 antibodies may activate irAEs, affecting lung, gastrointestinal tract, skin, liver, the endocrine system, and other organ systems.…”

Axitinib Reverses Resistance to Anti-Programmed Cell Death-1 Therapy in a Patient With Renal Cell Carcinoma

“…Antibodies targeting PD-1 or PD-L1 can block this inhibitory signaling pathway and reactivate the anti-tumor immune response. Presently, based on clinical data from many phase III clinical trials, an anti-PD-1 or anti-PD-L1 agent is part of the standard of care for most types of advanced malignancies ( 3 ).…”

Immune Checkpoints: Therapeutic Targets for Pituitary Tumors

“…Different immune checkpoints work together to regulate the immune system, which is a double-edged sword, and in physiological situations, these checkpoints are usually responsible for maintaining the immune response within the required physiological range and protecting the host from autoimmunity. In the presence of a tumor, immune checkpoints may be used to inhibit the activation of T cells, thereby preventing T cells from damaging tumor cells and eventually leading to tumor proliferation or migration [ 10 – 12 ] ( Figure 1 ). Thus, targeted immune checkpoint therapy is a new hot spot in tumor immunotherapy.…”