Mre11 Inhibition Reduces Extrachromosomal DNA Formation and Associated Immune Suppression in Gliomas Resulting in Enhanced Response to PD-L1 Inhibitor Therapy
Abstract
Fiscal Year 2021 (FY21) Peer Reviewed Cancer Research Program (PRCPR) Program Idea Award / Topic Area: Brain Cancer Gliomas are the most common and lethal of all primary adult brain tumors. The glioma immune microenvironment (GIM) plays a critical role in tumor development, progression, and prognosis. Several successful immune therapies have received recent approval from the Food and Drug Administration across various cancers, but the results for immune therapy against tumors in the brain have been less encouraging to date. These findings clearly indicate that gliomas must have a complex multimodal immunosuppressive mechanism that can’t be overcome by a single agent immunopotentiation mechanism. The question that remains is how to improve tumor immune recognition in the first place, and one suggested strategy is to combine factors that are suppressing the local immune interactions. Recent studies in gliomas demonstrated the presence of extra chromosomal circular DNA (eccDNA), which has been known as a potent stimulator of cGAS-STING pathway mediated immune activation for more than half a century. But gliomas with eccDNA were unable to generate immune responses, but rather act as a suppressor of the cGAS-STING pathway mediated immune activation. Generation of eccDNA depends on DNA resection at multiple levels and must be dependent on nucleases, a group of enzymes that is responsible for DNA resection. Mre11 has both exo- and endo-nuclease activity and is at the central of DNA end resection at various types of DNA damage repair pathway. Our preliminary studies demonstrated that pharmacological inhibition of Mre11 reduces generation of eccDNA and increases expression of genes of the innate immune pathway, suggesting a reversal from immune suppression toward immune potentiation. Although the overall glioma-associated immune suppression has been studied in detail, little is known about the mechanism of blocking the cGAS-STING pathway mediated immune activation. In addition, we believe that the eccDNA interact with cGAS-STING pathway, which leads to immune suppression. Therefore, the objective of this proposal is to develop a therapeutic regime that reduces extrachromosomal DNA formation, resulting in activation of glioma immune system and thereby, sensitizes glial tumors to immunotherapeutic approaches. We therefore hypothesize that Mre11 inhibitor reduces the formation of eccDNA and thereby, overcome cGAS-STING-mediated immune suppression resulting in enhanced sensitivity of glial tumors to PD-L1 inhibitor therapy. In this study, we will determine how Mre11 nuclease activity regulates generation of eccDNA. Next we will try to decipher how eccDNA suppresses cGAS-STING pathway. Finally, we want to use mouse intracranial glioma models to find out if pharmacological inhibition of Mre11 nuclease activity overcomes immune suppressive tumor microenvironment and subsequently increases therapeutic sensitivity of glial tumors toward immune check point inhibitors. FY21 PRCRP Overarching Challenge: Primarily, the proposed research will transform glioma treatment by targeting Mre11, a new target that will improve immune checkpoint inhibitor therapy. Secondly, this proposal will also help to understand the mechanisms of immune suppression associated with generation of eccDNA and its association in suppressing GIM. This project will lead to a promising outcome toward mission readiness in the FY21 PRCRP by filling gaps in developing new treatment options for gliomas. Our proposal, therefore, has the potential to rescue the immune suppressive state of glioma immune microenvironment by targeting Mre11, which can significantly enhance the outcome of PD-L1 inhibitor therapy in patients with glioma and, potentially, in other cancers. Relevance to Active-Duty Service Member: Various scientific literature suggests a relationship between military occupation and the development of brain tumors. Studies found a dif
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210662
Entities
People
- Joydeep Mukherjee
Organizations
- United States Army
- University of California, San Francisco