Role of tumor microenvironment in the regulation of PD-L1: A novel role in resistance to cancer immunotherapy.

Tumor evasion from the host immune system is a substantial strategy for tumor development and survival. The expression of many immune checkpoint proteins in cancer cells is a mechanism by which tumor cells escape from the immune system. Among the well-known immune checkpoints that can tremendously affect tumor development and cancer therapy are the programmed death-ligand-1/programmed death-1 (PD-L1/PD-1). To tackle this phenomenon and improve the therapeutic strategies in cancer treatment, the blockade of the PD-L1/PD-1 pathway is introduced as a target, but the therapeutic advantage of PD L1/PD-1 blockade has not fulfilled the expectations. This condition may be associated with a different type of resistance in a considerable number of patients. A crucial issue to conquer resistance against immune checkpoint blockade therapy is to understand how PD-L1 level is regulated. However, the mechanisms by which the PD-L1 expression is regulated are complicated, and they can occur at different levels from signaling pathways to posttranscriptional levels. For example, various transcriptional factors, such as hypoxia-inducible factor-1, nuclear factor-κΒ, interferon-γ, STAT3, MYC, and AP-1 can regulate the PD-L1 distribution at the transcriptional level. Herein, we tried to focus on the most important regulatory mechanisms of PD-L1 by inducible agents in the tumor cells, such as signaling pathways, transcriptional factors, and posttranscriptional factors. Finally, these approaches may open up new windows for targeting tumor immune evasion and suggest the novel suppressors of PD-L1 for efficient therapeutics.