Breakthrough discovery of signal cancers use to hide from immune system
Cancercells often deploy specific "don't eat me" signals to hide fromimmune cells. A breakthrough new study from Stanford University hashomed in on a previously undiscovered signaling protein that, ifeffectively 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 thehuman body, but cancer cells deploy a variety of strategies to hide fromthese hunters. One of these strategies is to express certainproteins that signal "don't eat me" to the macrophages.
Two of the earliest discovered signaling proteins used by cancercells 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 wasawarded 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 allpatients responded effectively to anti-CD47 treatments, suggestingthere must still be some significant signalingproteins yet to be discovered.
"Finding that not all patients responded to anti-CD47 antibodieshelped fuel our research at Stanford to test whether non-respondercells 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 thatseemed to be flourishing while in the presence of macrophages.This means they must be secreting some kind of signal to avoiddestruction from the nearby immune cells, and the search rapidly revealedthe culprit. CD24, a signaling protein not dissimilar to CD47,appeared in high volumes on the surface of cancer cells being ignoredby the macrophages.
Subsequent studies in human cells and animals confirmed that whenCD24 signaling was blocked, the immune cells suddenly switched onand went after the cancer cells. Even more interesting was thefinding that there seemed to be an inverse relationship in efficacybetween CD24 and CD47 blocking. This means cancers that didn'trespond effectively to CD47 blocking did respond well to CD24blocking, and vice versa. Ovarian and triple-negative breast cancerwere 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 leadauthor on the new study, Stanford PhD student Amira Barkal.
It's hoped the discovery of this major signaling protein willlead to new immunotherapy treatments that increase the number ofoptions that clinicians have at their disposal to help patients.Just as the discoveries of PD-1, CTLA-1 and CD47 have led to newlifesaving immunotherapy treatments, with time, so should this CD24 breakthrough.
"CD47 and CD24 were both discovered by graduate students inMD-PhD programs at Stanford along with other fellows," saysWeissman. "These started as fundamental basic discoveries, but theconnection to cancers and their escape from scavenger macrophages ledthe team to pursue preclinical tests of their potential. This showsthat combining investigation and medical training can acceleratepotential lifesaving discoveries."
The new research was published in the journal Nature.
Source: Stanford Medicine