A recent experiment in mice suggested that immune checkpoint therapies can get a boost if combined with other drugs targeting myeloid-derived suppressor cells, or MDSCs. These cells reach unusually high levels in people with cancer. Checkpoint therapies have helped thousands of people with some incurable cancers. In these therapies, the selected drugs release brakes on the immune system. However, these therapies have failed in many patients and work poorly for some cancers as the body's defense system can stall in more than one way.
The checkpoint blockers traditionally target a particular set of brakes: protein interactions that disarm the body’s T cells, allowing cancer to grow unchecked.
MDSCs are a mix of immature cells from the same family as neutrophils and macrophages, which act as general first responders in the immune system.
William Carson III, a surgical oncologist at Ohio State University in Columbus said that their normal function is to slow things down, as reported by sciencenews.org.
To test the idea, Andrew Stiff, a physician-researcher in Carson’s lab, conducted studies in mice with implanted breast tumors — a type of human cancer that responds poorly to checkpoint blockade. Among mice treated with the checkpoint blocker anti-PDL1, tumor growth slowed in three of 11 animals.
Mice treated with a placebo drug or Brd4 inhibitor alone fared worse. The third group of animals received combination therapy, anti-PDL1, and a Brd4 inhibitor, which aimed to release the brakes on T cells and curb the suppressor cells at the same time. Tumors shrank in seven of 11 of those mice, Stiff reported June 24 at the AACR meeting.
Treated mice had fewer MDSCs in circulation and at the tumor site. Other experiments suggested Brd4 inhibitors can influence MDSCs in several ways--including killing them directly or suppressing a molecule that drives their growth and expansion.
The team got similar results with several different Brd4 inhibitors and in mice with breast, colon or lung tumors. Though preliminary and unpublished, the findings suggest that Brd4 inhibitors “can get rid of these immune suppressor cells that are an additional brake on the immune system, and allow immune-stimulating drugs to work better,” says Carson.
The researchers reported their initial findings at the annual meeting of the American Association for Cancer Research, held virtually in late June.