2.3.1　PD-L1

As one of the major threats to public health worldwide, cancer is responsible for millions of deaths annually, with a high morbidity.Simultaneously, trillions of dollars spent in cancer treatment further intensify the pressure upon our society and patient families.Since the last decade, the immunotherapy has become an efficient cancer treatment.With the onset of tumor, multiple immune resistance mechanisms, such as local immune evasion, tolerance induction, and immune edition, are developed for tumor escape from immune surveillance.Thus, immunotherapy strategies against cancers are proposed to stimulate the effectors and/or counteract inhibitory and suppressive mechanisms, including the regulation of immune cells (vaccine and T cell engineering), cytokines (ILs,IFNs, TGFs, TNFs, etc.) and immune checkpoints.Recent discovery of immunosuppressive checkpoints,such as CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and PD-1, provides a very successful regimen to cancer immunotherapy, which has been awarded Nobel Prize in 2018 [31, 32].

PD-L1, also known as CD274 and B7-H1, is a transmembrane protein commonly expressed on the surface of antigen presenting cells and tumor cells.PD-L1 specifically binds to its receptor, PD-1,which is expressed on the surface of immune-related lymphocytes, such as T cells, B cells, and myeloid cells.In some solid or blood tumors, the PD-L1 can also bind to the PD-1 expressed on tumor cell surface.As shown in Figure 2.1, the binding of PD-L1 to PD-1would be able to activate the down-stream signaling of PD-1 receptor in T cells, thus inhibiting the proliferation, cytokine generation and release, and cytotoxicity of T cells.This down-regulation of immunity will prevent autoimmunity and chronic infection; many tumor cells also use this mechanism to protect themselves from immune attack, causing the so-called tumor immune evasion.PD-L1 mediated tumor immune resistance includes innate resistance caused by endogenously constitutive PD-L1 expression, and adaptive resistance caused by exogenously stimuli-inducible PD-L1 expression.Inhibition of either PD-1 or PD-L1 will enhance T cell responses to cancer.This approach is known as PD-1/PD-L1 based immunotherapy (Figure 2.1) [33-35].

Figure 2.1　Immunotherapy based on PD-1/PD-L1 interaction.(A) The interaction of PD-1/PD-L1 causes tumor immune tolerance.The PD-1/PD-L1 interaction stimulates the downstream signals to suppress T cell activation, resulting in tumor cell survival.(B) Breakdown of the PD-1/PD-L1 interaction reactivates T cells and related immune responses.Without the PD-1/PD-L1 interaction, the suppression signal is removed, thus leading to T cell activation, proliferation, and cytokine generation and tumor cell elimination.KIR, killer-cell immunoglobulin-like receptor.(Please scan the QR code on the Preface to get original color figures.)
Source: Wu Y, Chen W, Xu Z P, Gu W.“PD-L1 Distribution and Perspective for Cancer Immunotherapy-Blockade, Knockdown, or Inhibition”.FrontImmunol, 2019, 10:2022.(https://www.daowen.com)

Based on this understanding, six antagonists have been developed and successfully approved by the US FDA.The approved antagonists are monoclonal antibodies and have the ability to bind PD-1 or PD-L1.Notably, these antibodies demonstrate remarkably durable and persistent responses, with some patients remaining free from cancer progression for many years.A brief summary of applicable cancer types with PD-L1 antibody response is illustrated in Table 2.1.Despite the success achieved in PD-1/PD-L1 antibody therapies, the objective response is not as high in PD-L1 positive cohort, and some unexpected responses occurred in PD-L1 negative cohort.Further studies of PD-L1 reveal its intracellular and extracellular existence, leading to the idea of whether antibody therapy is the optimal solution in all cancer cases [36, 37].

Table 2.1　Applicable tumor types that respond to the US FDA proved PD-1/PD-L1 antibody products [34]