Discovered a key mechanism in the pancreatic tumor pathogenesis

In an article published on the prestigious journal Nature, the researchers of IRCCS San Raffaele Hospital demonstrated the importance of a subgroup of cells of the immune system – the macrophages IL-1β+ - in the progression of the ductal adenocarcinoma of pancreas (PDAC).

The scientific team – guided by Professor Renato Ostuni, group leader of the Genomics of the Innate Immune System laboratory at San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and associated professor at Vita-Salute San Raffaele University – discovered a new mechanism based on the interaction between the macrophages IL-1β+ and specific tumour cells that allows the tumour development.

The research – granted both by AIRC Foundation for the Research on Cancer, the European Research Council (ERC) and the Ministry of Health– suggests that blocking this interaction might be a new strategy to contrast the onset of pancreatic tumour in people at risk or to enhance the response to immunotherapy in those who already suffer from this disease.

The role of macrophages and inflammation in pancreatic tumour

Macrophages are cells of the innate immune system, essential to protect the integrity of tissues and to activate protective responses against pathogens and other external threats.  In tumours, however, the functions of macrophages are profoundly reprogrammed to the point that these cells support, rather than contrast, the progression of the pathology.

Macrophages associated to tumour (TAM) are important targets in immunotherapy, since their abundance is generally related to resistance to treatments, metastasis and a poor survival of patients. In the case of pancreatic tumour, however, the heterogeneity of TAM and the complexity of their interaction with microenvironment, has made it difficult to target the cells for therapeutic purposes.

“In addition to being characterized by a compromised immune system that limits the efficacy of even the most advanced immunotherapies, pancreatic tumour shows a strong inflammatory component”, says Renato Ostuni. “This is particularly relevant, since the onset of tissue damages – and the inflammatory responses that follow, such as pancreatitis – represent known risk factors for neoplastic development”.

On what the ability of inflammation to promote pancreatic tumour growth depended was until now unclear:: thanks to this study, researchers have defined one of the central mechanisms of this process.

San Raffaele research

p3lab_coverOstuni's group

Ostuni's group

Thanks to single-cell and spatial transcriptomics, which are able to reveal the molecular characteristics of thousands of single cells in their natural microenvironment, the scientific team guided by Ostuni identified, in patients suffering from pancreatic tumour, a new macrophages subgroup called IL-1β+ TAM. Researchers discovered that these cells are able to stimulate the aggressiveness of the closest tumor cells, inducing an inflammatory reprogramming and promoting release of factors that, in turn, promote the development and activation of IL-1β+ TAM themselves.

“It’s a sort of self-sustaining vicious circle. Macrophages make tumor cells more aggressive, and these cells reprogram macrophages to facilitate inflammation and disease development” explains Ostuni.

Research also showed that IL-1β+ TAM are not casually distributed, but they are localized in the smallest niches next to inflamed tumor cells. It’s actually this physical proximity that might encourage the progression of the pathology.

“We have conducted laboratory experiments to interfere with this circuit. Even though results are based on experimental models, they are encouraging. In fact, this approach has led first to a reduction of the inflammation progress, and secondly a delay in pancreatic tumor growth”, conclude Nicoletta Caronni and Francesco Vittoria, two of the main authors of the research.

Integration between competences

The study is the result of a close collaboration between researchers and physician at San Raffaele Hospital.

“This allowed us to study with advanced methodologies the characteristics of patient’s immune system, identifying new biological therapeutic targets” say professors Massimo Falconi, head of Pancreas Center, and Stefano Crippa, pancreatic surgeon of the same division.

The approach adopted by the scientific team headed by Ostuni has successfully tried to integrate the interpretation of the laboratory experiments with the data analysis thanks to bioinformatics. “An interdisciplinary and effective method, essential to conduct advanced scientific research”, conclude Federica Laterza and Giulia Barbiera, computational biologists and main authors of the study.

Future developments

Data from the newly published research suggest that blocking this inflammatory loop might increase immunotherapies efficacy against PDAC and, at the same time, might be used as a preventive strategy in people at risk.

“DNA mutations are necessary but not sufficient for tumors to develop. Inflammatory responses and tissue damage may cooperate with mutation to increase the risk of pancreatic tumors”, says Ostuni.

Researchers then conclude: “We have taken a big step in comprehending biological processes at the basis of this pathology. However, we are in a preclinical research stage that still is very distant from being applicated on patients. The up-coming years will be essential to identify potentialities and the most appropriated modalities to act on this new therapeutic target”.