Cancer cells often deploy specific "don't eat me" signals to hide from immune cells. A breakthrough new study from Stanford University has homed in on a previously undiscovered signaling protein that, if effectively inhibited, may lead to new treatments for breast, ovarian, and other difficult-to-treat cancers.

Macrophages are immune cells that seek and destroy cancers in the human body, but cancer cells deploy a variety of strategies to hide from these hunters. One of these strategies is to express certain proteins that signal "don't eat me" to the macrophages.

Two of the earliest discovered signaling proteins used by cancer cells to hide from macrophages are PD-1 and CTLA-4. Initially uncovered in the 1990s, their discovery led to the development of exciting and novel cancer immunotherapies. Just last year the Nobel Prize in Medicine was awarded to the two scientists behind this amazing breakthrough.

CD47 is a more recently discovered signaling protein currently being investigated in a number of different human clinical trials. The newly published research grew from the clinical observation that not all patients responded effectively to anti-CD47 treatments, suggesting there must still be some significant signaling proteins yet to be discovered.

"Finding that not all patients responded to anti-CD47 antibodies helped fuel our research at Stanford to test whether non-responder cells and patients might have alternative 'don't eat me' signals," says Irving Weissman, senior author on the new study.

The new research began by closely investigating cancer cells that seemed to be flourishing while in the presence of macrophages. This means they must be secreting some kind of signal to avoid destruction from the nearby immune cells, and the search rapidly revealed the culprit. CD24, a signaling protein not dissimilar to CD47, appeared in high volumes on the surface of cancer cells being ignored by the macrophages.

Subsequent studies in human cells and animals confirmed that when CD24 signaling was blocked, the immune cells suddenly switched on and went after the cancer cells. Even more interesting was the finding that there seemed to be an inverse relationship in efficacy between CD24 and CD47 blocking. This means cancers that didn't respond effectively to CD47 blocking did respond well to CD24 blocking, and vice versa. Ovarian and triple-negative breast cancer were specifically noted as responding well to the new CD24-blocking method.

"There are probably many major and minor 'don't eat me' signals, and CD24 seems to be one of the major ones," says lead author on the new study, Stanford PhD student Amira Barkal.

It's hoped the discovery of this major signaling protein will lead to new immunotherapy treatments that increase the number of options that clinicians have at their disposal to help patients. Just as the discoveries of PD-1, CTLA-1 and CD47 have led to new lifesaving immunotherapy treatments, with time, so should this CD24 breakthrough.

"CD47 and CD24 were both discovered by graduate students in MD-PhD programs at Stanford along with other fellows," says Weissman. "These started as fundamental basic discoveries, but the connection to cancers and their escape from scavenger macrophages led the team to pursue preclinical tests of their potential. This shows that combining investigation and medical training can accelerate potential lifesaving discoveries."

The new research was published in the journal Nature.