Modulating tumor PD-L1 expression is critical to improve researchers' understanding of tumor immune evasion and improve current anti-tumor immunotherapies. Recently, in a research report titled "CRISPR screening identifies the deubiquitylase ATXN3 as a PD-L1–positive regulator for tumor immune evasion" published in the international journal Journal of Clinical Investigation, scientists from Northwestern University and other institutions have identified a previously unknown tumor immune escape regulator through research, which may be expected to help improve the efficacy of current and future anti-tumor immunotherapies.
Figure 1. The deubiquitylase ATXN3 as a PD-L1–positive regulator for tumor immune evasion. (Wang S, et al., 2023)
"This study provides molecular insights into why some cancer patients cannot be treated with checkpoint blockade anti-tumor therapies," said researcher Dr. Deyu Fang. Anti-tumor immunotherapy is a special type of cancer therapy that helps the body's immune system fight cancer. It includes a range of therapy types, such as immune checkpoint inhibitors. Immune checkpoints help prevent the immune system from becoming too strong and destroying other cells, including cancer cells. By targeting these checkpoints with checkpoint inhibitor drugs, the immune system can better respond and fight off cancer cells. However, not all patients respond to immunotherapy, and the reasons behind this are currently unknown to researchers.
The big question now is whether researchers can find a better way to make the therapy effective for all patients. A common immune checkpoint protein targeted by anti-tumor immunotherapy drugs is PD-L1. It can be expressed on the surface of immune cells, and its expression will increase on the surface of some cancer cells, which may help them evade attack by the immune system. Therefore, identifying novel regulators of PD-L1 expression in tumors may help improve the efficacy of anti-tumor immunotherapy.
In the current study, the researchers developed a CRISPR-based screening platform to analyze the entire deubiquitination gene family from mouse and human PD-L1 lung cancer cell lines. Using this method, the researchers found that the ATXN3 gene can promote tumor immune evasion by promoting the expression of PD-L1 in tumor cells at the transcriptional level. After further analysis using The Cancer Genome Atlas database, the researchers revealed a positive association between the ATXN3 gene and CD274 in more than 80% of human cancers. Notably, there is a positive correlation between ATXN3 and the expression of PD-L1 and its transcription factor in human lung adenocarcinoma and melanoma.
The researchers stated that since ATNX3 can promote the expression of PD-L1, they proposed that inhibition of ATNX3 may enhance anti-tumor immunity in vivo. Using CRISPR and other targeted gene expression technologies to knock out the expression of ATNX3 in PD-L1 lung cancer mouse models, researchers have discovered that inhibiting ATNX3 expression may enhance anti-tumor immunity in mice and improve the efficacy of PD-1 antibody therapy. Research results indicate that ATNX3 is a positive regulator of PD-L1 tumor expression and tumor immune evasion. The study also points out that selectively targeting ATNX3 may improve the efficacy of anti-tumor immunotherapy and reduce toxicity and adverse side effects in all patients.
If researchers can combine ATNX3 inhibitors with current anti-tumor immunotherapies, they may be able to improve the efficacy of the treatments and reduce the number of antibodies needed, meaning patients would experience significantly fewer side effects from the treatment. In summary, the researchers identified the previously unknown deubiquitinating enzyme ATXN3 as a positive regulator of PD-L1 transcription and provided a certain theoretical basis for targeting ATXN3 to sensitize checkpoint blockade anti-tumor immunotherapy.
Reference
Wang S, et al. CRISPR screening identifies the deubiquitylase ATXN3 as a PD-L1–positive regulator for tumor immune evasion. Journal of Clinical Investigation, 2023, 133(23): e167728.