Posttranslational regulatory mechanism of PD-L1 in cancers and associated opportunities for novel small-molecule therapeutics

Abstract

Despite the tremendous progress in cancer research over the past few decades, effective therapeutic strategies are still urgently needed. Accumulating evidence suggests that immune checkpoints are the cause of tumor immune escape. PD-1/PD-L1 are among them. Posttranslational modification is the most critical step for protein function, and the regulation of PD-L1 by small molecules through posttranslational modification is highly valuable. In this review, we discuss the mechanisms of tumor cell immune escape and several posttranslational modifications associated with PD-L1 and describe examples in which small molecules can regulate PD-L1 through posttranslational modifications. Herein, we propose that the use of small molecule compounds that act by inhibiting PD-L1 through posttranslational modifications is a promising therapeutic approach with the potential to improve clinical outcomes for cancer patients.

1. Introduction

Immunotherapy, which refers to the state of hypo- or hyperimmunity in the body, artificially enhances or suppresses the body's immune function to achieve therapeutic disease treatment and is gradually becoming an important method for the treatment of cancer. Among numerous immunotherapeutic strategies, immune checkpoint blockade has shown clear advantages in the treatment of a range of cancers. Immune checkpoints increase antitumor immunity by blocking immune-related intrinsic downregulators, such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or its ligand programmed cell death ligand 1 (PD-L1). Among them, PD-1 is an immune checkpoint receptor that restricts T-cell effector functions in tissues. It has also been the research focus of tumor immunotherapy in recent years, and it is widely used in the clinic. PD-L1, a known PD-1 receptor, can be expressed in normal cells when combined with PD-1 in immune cells to circumvent the killing of immune cells, thus effectively preventing autoimmune diseases, and is expressed in cancer cells to induce immunosuppression and thereby promote immune escape.

Cancer immunotherapy is a therapeutic approach to reinitiate and maintain the tumor immune cycle and restore the body's antitumor immune response so that immune cells can recognize and kill tumor cells normally, thereby achieving control and clearance of tumor cells in the body. Common tumor immunotherapies include immune checkpoint inhibitors and adoptive cell therapies. In 2014, the first PD-1 monoclonal antibody, nivolumab, was approved for the treatment of melanoma [1,2]. To date, α-PD-1/PD-L1 therapy has shown potent antitumor activity in various cancers, such as melanoma, non-small cell lung cancer (NSCLC), gastric cancer, liver cancer, urothelial cancer, lymphoma, and all microsatellite instability (MSI)-high cancers. Immune checkpoint inhibitors (ICIs) have emerged as highly effective therapies for many cancers. All approved ICIs to date are mAbs, but mAbs, as a type of macromolecular therapeutic, suffer from many inherent drawbacks, including poor oral bioavailability, prolonged tissue retention and half-life, and poor membrane permeability, transport and storage. In addition, the higher cost of antibody drugs is also a nonnegligible issue. Therefore, downregulating the expression of PD-L1 in tumor cells using small molecule compounds is a very promising treatment option (Figure 1).