Researchers have discovered a “don’t eat me” signal that is deployed by ovarian and breast cancer cells to evade a person’s immune system. Similar to other anti-cancer therapies in use or under testing, blocking this signal raises hope for a new class of immunotherapies to combat these cancers.
A team at Stanford University’s School of Medicine found that ovarian and triple-negative breast cancer (TNBC) cells express particularly high levels of CD24 at their surface, which helps protect them from macrophages, a type of white blood cell that can “eat” cancer cells and clear them away.
Removal or blockade of CD24 restores the ability of macrophages to attack tumor cells, thereby slowing cancer growth in mice implanted with human tumors, the scientists found.
Their study, “CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy,” was published in the journal Nature.
Cancer cells can evade being recognized and killed by the immune system by displaying certain “don’t eat me” signals that shield them from immune cell attacks. Normally, these signals keep the immune system from mistakenly attacking healthy cells, but cancer cells harness this process to hide from the immune system.
Specifically, tumor cells can express proteins at their surface that stop macrophages (a type of white cell) from detecting, engulfing, and destroying cancer cells, in a biological process called phagocytosis.
Examples of such “don’t eat me” signals include CD47, programmed cell death ligand 1 (PD-L1), and beta-2 microglobulin subunit of the major histocompatibility class I complex (B2M).
Scientists have found that antibodies that block these signals render cancer cells more vulnerable to the immune system, and therefore these antibodies have therapeutic potential against several cancers.
For instance, cancer treatments targeting PD-L1 are already being used in the clinic. They belong to a class of anti-cancer therapies dubbed immune checkpoint inhibitors. In addition, antibodies that block CD47 are being tested in clinical trials for blood and solid tumors.
But variability in the strength and duration of these agents’ activity “has suggested the presence of additional, as yet unknown ‘don’t eat me’ signals,” the researchers wrote, a suspicion that prompted them to look for other such signals in tumors.
“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,” the study’s senior leader, Irving Weissman, MD, professor at Stanford Medicine said in a news release.
Weissman is the director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine and of the Ludwig Center for Cancer Stem Cell Research.
By studying human ovarian and breast cancer samples, the scientists saw that many of these cancers overproduced CD24 compared with normal cells and surrounding tissues; and that macrophages infiltrating these tumors sensed CD24 through a receptor called Siglec-10.
Lab experiments using cancer cell lines and tumor samples collected from ovarian and TNBC patients showed that if the interaction between CD24 and Siglec-10 was blocked with an antibody, then macrophages would start “gorging on” and eliminating cancer cells. Further studies in mice implanted with breast or ovarian cancer cells confirmed these results. When CD24 signaling was genetically removed from tumors in the mice, macrophages began to attach and “eat” cancer cells more avidly, delaying their growth.
The fact that ovarian cancer and TNBC, both difficult to treat, were highly affected by blocking CD24 signaling is a positive sign that targeting CD24 may be a promising strategy to fight these cancers.
“This may be a vulnerability for those very dangerous cancers,” said study leader, Amira Barkal, an MD-PhD student at Stanford Medicine.
Another interesting discovery was that some cancers, such as blood cancers, seem to be highly susceptible to blockage of CD47 but not CD24, while the opposite is true for other cancers, such as ovarian cancer.
This raises the possibility that both CD47 and CD24 are major “don’t eat me signals” and that most cancers would be vulnerable to therapies that block one of them. A therapy that blocks both may even offer a more powerful treatment to some cancers.
Based on their discovery, the scientists hope that therapies to block CD24 signaling can succeed in preclinical tests and then proceed to human clinical trials in the near future.