Researchers at Northwestern Medicine have identified a previously unknown regulator of tumor immune evasion, which could potentially improve the efficacy of current and future anti-tumor immunotherapies. The findings of the study were recently published in the Journal of Clinical Investigation.
The study provides valuable molecular insights into understanding why some cancer patients do not respond to checkpoint blockade antitumor therapy, while others do. Antitumor immunotherapy is a type of cancer treatment that involves boosting the patient’s own immune system to fight cancer. This can be achieved through different types of therapies, including immune checkpoint inhibitors. Immune checkpoints help to regulate the strength of the immune response, preventing the immune system from mistakenly attacking normal cells, including cancer cells.
Checkpoint inhibitors are drugs that target these checkpoints, allowing the immune system to recognize and attack cancer cells more effectively. However, not all patients respond positively to immunotherapy, and the underlying reasons for this have remained unclear.
The senior author of the study, Dr. Deyu Fang, explains that the ultimate goal is to find a better approach to make immunotherapy effective for all patients. In order to achieve this, the researchers focused on studying PD-L1, a protein that serves as a common immune checkpoint and is targeted by anti-tumor immunotherapy drugs. PD-L1 is expressed on immune cells and is found at increased levels on certain cancer cells, helping them evade the immune system.
Identifying novel regulators of PD-L1 expression in tumors could potentially enhance the efficacy of antitumor immunotherapies. To do this, the researchers developed a CRISPR-based screening platform to analyze the family of deubiquitination genes in both mice and human PD-L1 lung cancer cell lines. Through this approach, they discovered that the ATXN3 gene promotes tumor immune evasion by increasing 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 encodes PD-L1, in over 80% of human cancers. Notably, ATXN3 was found to be positively correlated with PD-L1 expression and its transcription factors in lung adenocarcinoma, the most common type of non-small cell lung cancer, as well as melanoma.
Based on the findings that ATXN3 promotes PD-L1 expression, the researchers hypothesize that suppressing ATXN3 could enhance antitumor immunity. To test this hypothesis, they used CRISPR and other gene expression techniques to knock out ATXN3 in mouse models of PD-L1 lung carcinoma. The results showed that suppressing ATXN3 enhanced antitumor immunity in the mice and improved the efficacy of PD-1 antibody therapy, indicating that ATXN3 is a positive regulator for PD-L1 tumor expression and immune evasion.
Dr. Fang suggests that selectively targeting ATXN3 could potentially improve the efficacy of antitumor immunotherapies while also reducing toxicity and adverse side effects for patients. By combining an ATXN3 inhibitor with current anti-tumor immunotherapy, the therapeutic efficacy can be enhanced, and the amount of antibody needed can be reduced, thereby minimizing side effects.
The findings of this study open up new possibilities for enhancing the effectiveness of immunotherapy and improving outcomes for cancer patients. Further research and clinical trials are needed to fully explore the potential of ATXN3 as a therapeutic target in the field of cancer immunotherapy.
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1. Source: Coherent Market Insights, Public sources, Desk research
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