Circulating immune cells and cancer, novel insights might lead the way to optimizing diagnosis and treatment

The MET-proto-oncogene is involved in the pathogenesis of several tumors and therefore represents an interesting target for future therapies. You examined the role of MET in tumors, what did you find?
Veronica Finisguerra: Little was known about MET expression and function in tumor immunity. This is important because immune cells can restrain the growth and spread of malignant cells, but can also foster tumor development and metastasis. We showed that MET is induced by TNF-α during pathophysiological inflammation such as skin rash, peritonitis and cancer. MET is then required for HGF-dependent neutrophil migration through the vessel wall of inflamed tissues, where neutrophils exert anti-microbial and anti-tumoral functions. From an immunological point of view, this highlights a clever and fine control of non-specific immune reactions, which is necessary in order to prevent damage to healthy organs and, conversely, to confine this cytotoxic response to the site of inflammation.

Andrea Casazza: From a therapeutic point of view, it indicates that MET inhibitors could have a double-edged effect on tumors: on the one hand, when acting on cancer cells that rely on MET hyperactivation for growth and survival, MET inhibitors would encourage cell-cycle arrest or cell death; on the other hand, when acting on neutrophils, they would crucially blunt pro-inflammatory, anti-tumorigenic reactions. In this way, this work indicates that patients should be enrolled in clinical trials with anti-MET drugs based on MET expression and dependency of the cancer cell itself, excluding those patients that have high MET expression in the immune infiltrate.

“This unique potential makes it a valid tool for patient follow-up after the primary tumor has been removed through surgery. And this through a simple blood test.”
Max Mazzone

How important are these results?
Max Mazzone: These findings are very important, because it affects a drug that is currently in clinical trials in which more than 15 companies are involved. Our results may be used to improve the efficacy of more than 20 drugs in preclinical trials and in phase I to phase III clinical trials based on patient stratification. Following systemic administration of a MET kinase inhibitor, we prove that the therapeutic benefit of MET targeting in cancer cells is partly countered by the pro-tumoral effect rising from MET blockade in neutrophils. Our work identifies an unprecedented role of MET in neutrophils and suggests a potential “Achilles’ heel” of MET-targeted therapies in cancer.

Can you tell us more about the Gut paper on colorectal cancer you wrote together with colleagues from UZ Leuven and the Nucleomics Core Facility?
If we are affected by cancer, our immune system responds to this and tries to remove the cancer cells from our body. A specific role in this process is assigned to the peripheral blood monocyte. From the moment that colorectal cancer cells are present in the body, substances secreted by the cancer cells activate specific genes of the peripheral blood monocytes.
For the identification of the genes involved in this process, Hans Prenen (UZ Leuven) and his colleagues from oncology centers in Brussels, Heidelberg and Rome collected samples from patients. This allowed us to identify 43 relevant genes. These are still too many genes to incorporate in a diagnostic test. Together with Wouter Van Delm (Nucleomics Core Facility) we eventually succeeded in creating a set of 23 genes with the same predictive value. We are still trying to reduce this number further.

What would be the added value of this test?
Colorectal cancer is very treatable if it is detected at an early stage, with approximately 95 % chance of a cure. If detected at a late stage, the chance of surviving 5 years after diagnosis is less than 10 %. This new test will probably make an earlier diagnosis possible, because it detects tumor-induced changes directly and not merely blood in the stools. This will increase the chances of a cure.
An additional benefit is that this process takes place at a point when the tumor is forming, the earliest stage of tumor development. Since this test is based on how our body reacts to the presence of colorectal cancer cells, it can also be used to detect distant metastasis even after the primary tumor has been removed. This unique potential makes it a valid tool for patient follow-up after the primary tumor has been removed through surgery. And this through a simple blood test. We hope to find an industrial partner who can help us develop this test very soon.

Finisguerra et al., Nature 2015
Hamm et al., Gut 2015