A new regulator of immune evasion in cancer identified

Northwestern Medicine researchers have identified a previously unknown regulator of tumor immune evasion that could help improve the effectiveness of current and future tumor immunotherapies, according to recent findings published in the journal Journal of Clinical Investigation.

“The study provides molecular insight into understanding why some cancer patients cannot be treated with checkpoint blockade antitumor therapy, while others can,” said Deyu Fang. , Ph.D., Hosmer Allen Johnson Professor of Pathology and senior author of the study. .

Anti-tumor immunotherapy is a type of cancer treatment that helps the immune system fight cancer and includes a range of types of therapies, such as immune checkpoint inhibitors. Immune checkpoints help prevent the immune system from becoming too strong and eradicating other cells, including cancer cells.

By targeting these checkpoints with checkpoint inhibitor drugs, the immune system can better respond and fight cancer cells. However, not all patients will respond well to immunotherapy and the underlying reason remains unclear.

“The big question is whether we can find a better approach to make this therapy work for all patients,” Fang said.

A common immune checkpoint protein targeted by antitumor immunotherapy drugs is PD-L1, which is expressed on the surface of immune cells and is also increased on the surface of some cancer cells, helping them evade the immune system .

Therefore, identifying novel regulators of PD-L1 expression in tumors could improve the effectiveness of antitumor immunotherapies, according to Fang.

In the present study, Fang’s team developed a CRISPR-based screening platform to analyze the entire family of deubiquitination genes from mouse and human PD-L1 lung cancer cell lines. Using this approach, researchers discovered that the ATXN3 gene promotes tumor immune evasion by promoting PD-L1 expression in tumor cells at the transcriptional level.

Further analysis using the Cancer Genome Atlas database revealed a positive correlation between the ATXN3 and CD274 genes, which encode PD-L1, in more than 80% of human cancers. Notably, ATXN3 was positively correlated with the expression of PD-L1 and its transcription factors in lung adenocarcinoma, the most common type of non-small cell lung cancer, and melanoma.

“Since ATNX3 promotes PD-L1 expression, we posited that deletion of ATXN3 could enhance antitumor immunity in vivo,” said Fang, who is also a member of the Robert H. Lurie Comprehensive Cancer Center. Northwestern University.

Using CRISPR and other targeted gene expression techniques to knock out ATXN3 in mouse models of PD-L1 lung carcinoma, researchers found that knocking out ATXN3 enhanced antitumor immunity in mice and improved the efficacy of PD-1 antibody treatment.

Results suggest that ATXN3 is a positive regulator of tumor PD-L1 expression and tumor immune evasion. According to Fang, the results also suggest that selective targeting of ATXN3 could improve the effectiveness of anti-tumor immunotherapies as well as reduce toxicity and unwanted side effects for all patients.

“If we combine an ATXN3 inhibitor and current anti-tumor immunotherapy, we can improve therapeutic efficacy and reduce the amount of antibodies needed, which means reducing side effects,” Fang said.