PD-L1 Distribution and Perspective for Cancer Immunotherapy-Blockade, Knockdown, or Inhibition

Abstract

Cancer immunotherapy involves blocking the interactions between the PD-1/PD-L1 immune checkpoints with antibodies. This has shown unprecedented positive outcomes in clinics. Particularly, the PD-L1 antibody therapy has shown the efficiency in blocking membrane PD-L1 and efficacy in treating some advanced carcinoma. However, this therapy has limited effects on many solid tumors, suspecting to be relevant to PD-L1 located in other cellular compartments, where they play additional roles and are associated with poor prognosis. In this review, we highlight the advances of 3 current strategies on PD-1/PD-L1 based immunotherapy, summarize cellular distribution of PD-L1, and review the versatile functions of intracellular PD-L1. The intracellular distribution and function of PD-L1 may indicate why not all antibody blockade is able to fully stop PD-L1 biological functions and effectively inhibit tumor growth. In this regard, gene silencing may have advantages over antibody blockade on suppression of PD-L1 sources and functions. Apart from cancer cells, PD-L1 silencing on host immune cells such as APC and DC can also enhance T cell immunity, leading to tumor clearance. Moreover, the molecular regulation of PD-L1 expression in cells is being elucidated, which helps identify potential therapeutic molecules to target PD-L1 production and improve clinical outcomes. Based on our understandings of PD-L1 distribution, regulation, and function, we prospect that the more effective PD-L1-based cancer immunotherapy will be combination therapies.

Keywords: PD-1/PD-L1 immune checkpoint; PD-L1 regulation; cancer immunotherapy; cellular PD-L1 distribution; combination therapy; gene silencing; signaling pathway inhibitor.

Figures

Figure 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.

Figure 2

Illustration of different PD-L1 formats. (A) mPD-L1, located on the tumor cell membrane, is able to bind with PD-1 on T cells and response to tumor immune escape. PD-L1 antibody competitively binding to mPD-L1 breaks the tolerance, leading to tumor cell clearance. (B) cPD-L1 is located in cytoplasm, and potentiates to transfer to mPD-L1. (C) nPD-L1 is located in nuclei. Its aberrant upregulation is speculated to be associated with promoted cell chemo-resistance. (D) sPD-L1 refers to its soluble format in the serum, generated from either endogenous secretion or cleaved fraction of mPD-L1s. Both host cells (such as APC and DC) and tumor cells can be the source of sPD-L1. PD-L1 antibody therapeutic effect is limited to sPD-L1 consumption, and cannot modulate intracellular PD-L1.

Figure 3

Signaling pathways of PD-L1 regulation. The instinct PD-L1 expression is regulated by translational factors (HIF-1α, NF-κB, AP-1, and STATs) that binds to the gene promoter. The extracellular signals (hypoxia, cytokines, and EGF signals) will be transduced via different pathways (mainly through MAPK or PI3K/AKT) to regulate PD-L1 expression on transcriptional level. Some miRs are able to bind to 3′-UTR of PD-L1 mRNA for post transcriptional regulation.

Figure 4

The personalized PD-L1 combination therapy, a prospect of optimal PD-L1 immunotherapy guided by PD-L1 distribution and immune resistance of patients. Innate immune resistant cohort: (A) for cells with high constitutive mPD-L1, the regimen would mainly rely on antibody blockade while the combination of gene silencing or chemical inhibitor would benefit the treatment. (B) For cells with high intracellular PD-L1, the regimen should more rely on gene knockdown or inhibition method, supported by PD-L1 antibody. Adaptive immune resistant cohort: (C) the inducible PD-L1 is much easier to be controlled by gene silencing and chemical inhibitor combination therapy. Combined immune resistance cohort: (D) for cells with both high constitutive and inducible PD-L1, the regimen would be better to choose the combination of antibody + gene silencing or antibody + chemical inhibitor.