Abstract
Although dendritic cells are abundant in ovarian tumors, scientists have been puzzled that these cells aren't immunostimulatory. New research reveals a role for the protein SATB1, which is transiently required during ovarian-associated dendritic cell maturation—its unremitting expression in these cells drives them to acquire an inflammatory, immunosuppressive phenotype.
Responsible for presenting foreign material to cytotoxic T cells, dendritic cells are abundant in ovarian cancer, yet these tumors still dodge immune surveillance: Instead of stimulating antitumor immunity, these ovarian-associated dendritic cells are naturally immunosuppressive. Now, researchers at the Wistar Institute in Philadelphia, PA, have uncovered some of the molecular players driving this phenotype.
“Previously, we'd found that delivering miR-155 to ovarian-associated dendritic cells silences a protein called SATB1, and this transforms the cells from immunosuppressive to immunostimulatory,” explains the study's senior author, José Conejo-Garcia, MD, PhD. “So, we decided to look more closely at how SATB1 impacts dendritic cell behavior in ovarian tumors.”
SATB1 creates loops in chromatin, bringing together transcriptionally active regions that would otherwise be far apart. It also oversees the recruitment of key epigenetic modifiers and transcription factors. Essentially, “SATB1 is a master genomic organizer,” Conejo-Garcia says, and he and his team reasoned that its influence would likely be significant.
After discovering that SATB1 is overexpressed in human and mouse ovarian-associated dendritic cells, “we initially figured it was a bad guy,” Conejo-Garcia says. “Then we started investigating its function, and what we found was quite illuminating, if also in the opposite direction of our original hypothesis.”
When they studied mice lacking SATB1, the researchers found that it is necessary for dendritic cells to mature and become immunocompetent. The latter is evidenced by MHC II expression, which is “what defines an antigen-presenting cell,” Conejo-Garcia notes—MHC II molecules interact with helper T cells, thereby triggering an immune response.
Further experiments revealed an intermediate, previously unknown role for NOTCH1 in the maturation of ovarian-associated dendritic cells. “SATB1 binds directly to the Notch1 promoter, and activated NOTCH1 then drives MHC II expression,” Conejo-Garcia says.
“The key here is that the window during which SATB1 is required is very narrow,” he explains. “Once dendritic cells have matured, SATB1 should disappear.” Instead, SATB1 persists in ovarian-associated dendritic cells, and its unremitting expression provokes the cells to produce multiple inflammatory and immunosuppressive molecules, including galectin-1 and IL6. When the researchers developed RNA-interfering nanoparticles to silence SATB1 in these cells, they observed that the cells not only were less inflamed, but also had enhanced antitumor immunity.
SATB1, then, is neither bad nor good, Conejo-Garcia says—like most cellular signaling proteins, “it's important, but only in moderation.”
Last summer, Juan Cubillos-Ruiz, PhD, and his group at Weill Cornell Medicine in New York, NY, showed that constitutive activation of a protein called XBP1 in ovarian-associated dendritic cells drives cancer progression by blunting antitumor immunity. He thinks the discovery of SATB1 as an additional player capable of tamping down antitumor immunity is “a key advance” that dovetails with his work.
Conejo-Garcia and his team “have not only identified novel functions for SATB1,” Cubillos-Ruiz adds, “they've also demonstrated the feasibility and significant immunotherapeutic potential of using nanotechnology to target this protein in ovarian-associated dendritic cells.” –Alissa Poh