Suppression of Innate Immunity in Ovarian Carcinogenesis
Abstract
The project is to test a hypothesis linking immune suppression and genomic rearrangement in ovarian cancer progression. The project may be relevant to the areas on etiology, epidemiology and prevention, and treatment resistance. The proposal is to test a provocative idea that potentially provides an explanation for the findings from the sequencing of cancer genome that massive changes occur in the non-coding regions of the ovarian cancer genome. Another idea to be tested is that immune suppression is linked to genomic rearrangement in ovarian cancer progression. The only commonly mutated gene in high-grade serous ovarian cancer is the tumor suppressor p53. Additionally, the ovarian cancer genome has extensive rearrangements in non-coding regions, but the cause and significance of these widespread genomic rearrangements have not been established. Nearly half of the entire human genome consists of sequences that resemble various viruses. Some of these sequences, known as transposable elements (DNA transposons, retrotransposons, or retroelements), can occasionally replicate and re-insert into genomic DNA. Our preliminary observation suggests a mechanism on how immunosuppression allows the unleashing of endogenous viral elements that can alter the genome of affected cells and promote cancer development. Normally, our innate immunity senses the presence of short DNA strings from viruses and microbes and then responds to purge the infected cells. We speculate that endogenous retroelements and transposons are also recognized by the immune system, and that is why normally endogenous retroelements and transposons are not active. Recently we found a gene, Sting (STimulator of INterferon Genes), that is critical for sensing the presence of short cellular DNA derived from viruses, microbes, and likely also the retroelements and transposons. Sting works in a pathway involved with several other proteins (one of them is cGAS) that sense the presence of short DNA inside a cell, but outside the nuclei, and activates genes for immune response. In preliminary study, we have found that the expression Sting and other components of the cellular DNA sensing pathway (such as cGAS) is lost in most ovarian cancer cell lines, but is present in normal cells, and we consider that loss of Sting accounts for the weakened innate immune response and thus activation of retroelements and transposons, which leads to genomic changes, accelerated clonal evolution, and consequently progression of ovarian cancer. We plan to test this idea in this project, and hope to make a finding that explains both the weak immune system and massive genetic changes in ovarian cancer. Potentially, we may be able to identify the activation of transposable elements in our genome, the enemies within, by loss of innate immunity (one way is the loss of STING expression), as an etiology of ovarian cancer development. The project is significant because of finding a link between the immune system and genetic changes in ovarian cancer. Although the finding may solve an important basic question in ovarian cancer development--the gain of massive genomic changes--the finding may also lead to practical application. One potential idea is to use this knowledge in guiding immunotherapy, such as restoring the Sting innate immunity pathway to prevent genomic changes. Another idea is to target the immune deficient, transposon-containing cancer cells with oncolytic therapy using engineered virus that is only capable of replicating in the cancer cells. The research may benefit women without cancer in preventive immune therapy, and also benefit cancer patients using viral therapy in treatment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810129
Entities
People
- Xiang-Xi Xu
Organizations
- United States Army
- University of Miami