Pancreas and colorectal cancer: a dual-action molecule for ‘cold tumours’ is on the way

Even the tumours least responsive to immunotherapy – the fourth pillar of cancer treatment – may have an Achilles’ heel. And science may be beginning to identify strategies to attack them precisely at that point, or rather at those points. There is a glimmer of hope (we are really only at the very beginning) that we might be able to lift the veil of insensitivity that effectively shields certain types of tumour – termed ‘cold’ tumours – from the immune system’s defensive action. A study published in *Cancer Research*, conducted by experts from the Universities of Cambridge and Basel, suggests the possibility of acting as a ‘booster’ for immunotherapy drugs, thanks to small molecules capable of enhancing their activity. These compounds have a dual action: on the one hand, they stimulate macrophages (essentially the ‘scavengers’ of our immune system) to engulf and phagocytose cancer cells; on the other, they modify the surrounding tissue, reducing its ability to suppress the body’s attacks on the tumour. It must be said, however, that so far this approach has only been tested in cell cultures and in zebrafish and mouse models with various types of tumour. But there is cause for hope.

The strategy could prove crucial precisely against ‘cold’ tumours – so called because they are capable of protecting themselves from attacks by the immune system and are therefore often resistant to drugs that act in this way. “The term ‘cold tumours’ refers to those neoplasms that manage to create a microenvironment poor in active immune cells, and are therefore difficult for our defences to recognise,” explains Paolo Tralongo, president of CIPOMO (Italian College of Chief Hospital Medical Oncologists) and director of medical oncology at Syracuse Hospital. “The tumour microenvironment is where it is determined whether the immune system will be able to mount an effective response against the disease. We can think of it as a sort of biological frontier or customs post: it is there that the signals are transmitted which allow immune cells to spring into action or, conversely, to hold back. Among the ‘cold’ tumours that most frequently display these characteristics are pancreatic cancer, the majority of microsatellite-stable (MSS) colorectal cancers, many prostate cancers and certain forms of breast cancer. Precisely because the immune system struggles to recognise them, these tumours respond less well to current immunotherapies.”

The study, coordinated by Gregor Hutter of the University of Basel and Basel University Hospital and Gonçalo Bernardes of the University of Cambridge (first author Valerio Sabatino), focuses on PSEs – an acronym standing for ‘Phagocytic Synapse Enhancers’. These small molecules act as a sort of ‘cable’ that connects the cells destined to ‘eat’ the tumour cells, triggering the process, “thanks to a sort of molecular bridge that links tumour cells and macrophages, signalling the latter to attack”, as Sabatino himself explains in a press release from the Swiss university. But that’s not all. In practice, PSEs induce macrophages to internalise and degrade the PD-L1 protein present on their surface, thereby altering the tumour microenvironment in the body’s favour and thus aiding the immune system. PD-L1 therefore plays a dual key role: it acts as a ‘stop signal’ for the immune system’s T-lymphocytes, preventing them from attacking the tumour. In effect, this approach turns the tables: it shifts from a ‘habitat’ that supports tumour growth to one that combats it.

At present, the approach has only been tested in the laboratory, so we are still a long way off. The strategy is nevertheless truly fascinating, because it effectively causes the body’s own cells to ‘betray’ the tumour. “Immunotherapy has focused almost exclusively on T cells, but myeloid cells, which dominate most solid tumours, were the missing piece of the jigsaw,” says Bernardes. “Our work shows that they can be reprogrammed to attack the tumour rather than protect it.” In any case, the findings offer cause for optimism: a particular long-lasting variant of PSE has slowed tumour growth more effectively than the comparator treatments. Above all, it is hoped that in future, PSEs can be tailored according to the cellular or molecular target to be attacked, as well as the type of tumour. “Our long-term vision is to design CAR T-cells for cancer therapy that not only attack the tumour directly, but also release PSE molecules into it to activate macrophages,” comments Hutter. “However, much more research will be needed before PSEs can be tested in clinical trials.” “The value of this study lies not in announcing a new therapy that is already available, but in opening up a different avenue,” concludes Tralongo. If, in the future, we really do manage to make tumours that currently evade the immune system’s control ‘visible’ to it, we will be able to expand the number of patients eligible for immunotherapy. It is important to remember, however, that we are still at the preclinical research stage: the results are promising, but they will need to be confirmed by clinical trials before they can change everyday practice.”