Our cells express specific proteins on their membranes – also called 'don't eat me' proteins – that tell the immune system to avoid attacking and ingesting them. These proteins are essential for preserving tissues from auto-immune pathologies, but they are also exploited by cancer cells, which over-expose them to become invisible to immune defenses.

A group of researchers of IRCCS Ospedale San Raffaele, coordinated by Marco Bianchi – leader of the Chromatin Dynamics research unit and full professor at Vita-Salute San Raffaele University – discovered a mechanism that prompts cancer cells to retract one of the key 'don't eat me' proteins, called CD47, therefore exposing cancer cells to controls by the immune system. The researchers also showed in an experimental model of mesothelioma (a very aggressive tumor resulting mainly from exposure to asbestos) that a synthetic molecule developed in their laboratory and called BoxA is able to activate the mechanism.

The results of the study, published in EMBO Molecular Medicine, pave the way for new cancer immunotherapy strategies that could facilitate cancer cell recognition and elimination.

 

Tissue proliferation and immune surveillance

Our organism, like all multicellular organisms, survives thanks to the ability of the its components – cells and tissues – to remain in equilibrium with each other. This equilibrium is often maintained by a multiplicity of contrasting signals, working as checks and balances.

One example concerns CD47, the main 'don't eat me' protein on the cell membrane. CD47 functions as a flag that alerts macrophages not to ingest (“phagocytize”) the cells on which it is exposed. All cells that are foreign to our body do not have CD47 and therefore are “legitimate game” for macrophages, while old cells withdraw CD47 spontaneously from their surface in order to get eliminated.

Researchers at San Raffaele discovered a situation in which the CD47 protein is retracted by tumor cells, which, unlike old cells, actively duplicate and cause uncontrolled tumor growth. According to the researchers' findings, it is precisely one of the signals that promotes their growth that causes CD47 to be retracted. The tumor cells are thus exposed to control by macrophages, which recognize them as “legitimate game” and present them to the rest of the immune system.

"The fact that some cells retract the 'don't eat me' signal from their surface when they proliferate makes perfect evolutionary sense," explains Rosanna Mezzapelle, first author of the study. "It is a safety check against the emergence of uncontrolled cell growth, i.e. tumors. The cells that grow the most are more tightly controlled. This mechanism, like others of its kind, is not infallible, but it can be boosted – at least in principle – by stimulating it in a controlled way."

 

The anti-tumor capacity of BoxA

The molecule that allows regulated activation of this “immunogenic surrender” mechanism in tumor cells is called BoxA. It is a synthetic molecule developed by Bianchi's group, the result of 20 years of research.

"BoxA is a small portion of a larger protein contained in the nucleus of our cells and called HMGB1," explains Marco Bianchi. "In the experiments we conducted, both in vitro and in animal models of mesothelioma and colon carcinoma, we showed that BoxA is able to cause the internalization of CD47 and thus to make tumor cells more visible to the immune system. And more importantly: it does this without promoting tumor growth, but rather slowing down its progression.”

The molecule so far has only been used in laboratory studies but has an excellent toxicity profile, making it an ideal candidate for clinical testing. "The long-term goal is to develop therapeutic strategies that make tumor cells more visible, acting in a complementary way to the immunotherapies already in use, such as immune checkpoint inhibitors," Bianchi concludes.