Nat commun: blocking Siah 2 enhances the antitumor immune response of PD-1 inhibitors

January 23, 2020 / BIOON / - -- in a new study, researchers from the Sanford Burnham prebys medical discovery Institute and the New York University School of Medicine found a new way to improve the immune system's ability to fight cancer Using a mouse model, they identified that siah2 protein plays an important role in controlling a class of immune cells called regulatory T cells (Tregs), which limits the effectiveness of immunotherapy currently used The relevant research results were recently published in the Journal of nature communications, with the title of "siah2 control of T-regulatory cell limits anti tumor immunity" Image from Wikipedia / cc by-sa 3.0 "Although siah2 is involved in controlling events that regulate cancer production, this study provides the first direct evidence of its role in the anti-tumor immune response of the immune system," said ze'ev Ronai, Ph.D., co-author of the paper and researcher of Sanford Burnham pribes medical discovery Institute Our study shows that PD-1 inhibitors can be used to treat tumors that are not responding to siah2 gene in mice, thus providing a means to expand the effectiveness of immunotherapy These findings also provide a further reason for our efforts to find a drug that can block siah2 " Cancer immunotherapy uses the power of the human immune system to destroy tumors Such therapies have revolutionized the treatment of some cancers For some people with advanced melanoma, the treatment extends the survival of these patients to years rather than months However, this treatment is only effective in about 40% of patients with advanced melanoma The new study provides a new way to make the treatment effective in patients who are currently unresponsive to the drug PD-1 "In our study, mice lacking the siah2 gene were able to initiate an immune attack against melanoma," Ronai explained In addition, the effectiveness of siah2 in immunotherapy has been demonstrated in 'cold' tumors, tumors that do not respond to immunotherapy: in siah2 mutant mice, PD-1 blockade can effectively clear these tumors " "Understanding the basic mechanism of tumor immune response will help us improve the effectiveness of immunotherapy," said Dr Michael rope, a professor of cell and developmental biology at the University of California, Kerry This new study reveals an important link in the regulation of key immune cell components that affect the effectiveness of cancer immunotherapy, thus highlighting the need to develop Treg cell inhibitors, in which siah2 inhibitors are expected to play a role " For many years, scientists have known that siah2 is involved in the cell's response to two processes - hypoxia and unfolded protein response - that tumors use to maintain growth Ronai has been working on the protein for nearly a decade in the hope of finding better cancer treatments: his team is currently working on a small molecule drug that blocks the protein Now, this new study shows that the protein also plays an important role in regulating the immune system's response to tumors In the new study, Ronai's team used genetically engineered mice that didn't produce siah2 protein, and then implanted melanoma with BRAF mutations, which occur in about half of human melanoma This approach allows them to study the role of siah2 in the tumor microenvironment In the absence of the siah2 gene, the melanoma subsided, whereas in mice with the siah2 gene, the tumor continued to grow Providing anti-PD-1 drugs to these mice effectively removed the melanoma that was originally resistant to this therapy, so this shows a new way to enhance the effectiveness of current immunotherapy Through in-depth study of these findings, the Ronai team found that in siah2 mutant mice, melanoma was infiltrated by killer T cells rather than Treg cells, indicating that the immune system was more active in tumor clearance The lack of Treg cells is due to the role of Siah 2 and its control over cell cycle regulatory proteins, resulting in their proliferation and their recruitment into tumors "Our findings will only inspire a sense of urgency in our search for drugs that inhibit siah2," Ronai said Using a range of new methods should allow us to accelerate the development of methods targeting siah2 in tumors and their microenvironment " (BIOON Com) reference: 1 Marzia scortegagna et al Siah2 control of T-regulatory cells limits anti tumor immunity Nature communications, 2020, doi:10.1038/s41467-019-13826-7 2.Study reveals a new approach to enhancing response to immunotherapy in melanoma https://medicalxpress.com/news/2020-01-reveals-approach-response-immunotherapy-melanoma.html