Dual targeting approach improves immunotherapy response in glioblastoma

Researchers from The University of Texas MD Anderson Cancer Center have found that simultaneously blocking two key “don’t eat me signals” found in cancer cells heightens the immune response and sensitizes tumors to immunotherapy in models of glioblastoma (GBM), highlighting a promising strategy.

The study, published in Nature Communications, was co-led by Wen Jiang, M.D., Ph.D., associate professor of Radiation Oncology, and Betty Kim, M.D., Ph.D., professor of Neurosurgery and core member of the James P. Allison Institute.

“Blocking these signals together resulted in a heightened immune response, suggesting this is like a one-two punch in order to get optimal results,” Jiang said. “It’s like unmasking the invisibility cloak from cancer so that T cells can better recognize tumor-derived antigens and allow immunotherapy to work more effectively.”

How cancer cells evade macrophages

Macrophages are immune cells that are part of our body’s immune system. They are known as important “first responders” that can recognize and engulf cancer cells, a process known as phagocytosis. Once they destroy cancer cells, they also share pieces of the tumor—known as antigens—with other immune cells such as T cells, to alert and educate them on how to recognize and infiltrate tumors.

However, cancer cells can often hide from these macrophages via proteins that act as “don’t eat me” signals, such as CD47. While CD47 is important for protecting healthy cells from being eliminated by the body’s own immune system, it is often overexpressed in many cancer cells as well, allowing tumor cells to hijack this system to avoid immune detection.

GBM, one of the most aggressive and deadly forms of brain cancer, is notoriously difficult to treat. While many cancers respond to immunotherapy, the GBM tumor microenvironment is considered immunologically “cold.”

Some studies have looked at blocking the CD47 “don’t eat me” signal while also giving patients immunotherapy. However, while this approach works for certain bloodborne tumors, it is not effective in solid tumors.

Dual blockade of CD47 and CD24

In this study, the researchers found another “don’t eat me” signal—CD24—which is also highly expressed in GBM tumors, and examined the effects of blocking CD47 and CD24 both individually and at the same time along with immunotherapy.

Blocking both CD47 and CD24 at the same time worked much better at improving immunotherapy response in GBM models compared to blocking each arm individually.

Targeting both signals allows macrophages to better recognize and attack cancer cells, which then present antigens for other T cells and allow immunotherapy to work more effectively.

Redundant escape routes and next steps

“We’re still trying to understand this area of innate immune system-driven therapies and how these first responders clear up cancer cells,” Kim said.

“But what we are observing is that cancers are smart in that they have developed redundant strategies to evade our body’s system. Eliminating one pathway is often insufficient to eradicate them. This is another step toward the ultimate goal of making tumors that may or may not respond to traditional therapies respond just that much more.”

While further evaluation is needed, the next step for this approach is to identify suitable CD47 and CD24 blockade therapies. Several CD47-targeting agents are already in clinical trials, whereas CD24-directed therapies are still in early-phase development.