Pancreatic cancer is one of the big killers of oncology, the fourth cause of death from cancer in the Western world. The intrinsic aggressiveness of the tumor, the often late diagnoses linked to the absence of symptoms in the initial stages, and the fact that it tends to resist the most innovative pharmacological therapies contribute to making it so serious. However, a discovery comes from San Raffaele in Milan that could help develop new therapeutic approaches. The research, described on the pages of Nature, in fact, clarifies one of the mechanisms that allow pancreatic cancer to exploit our immune system to fuel its growth, identifying IL-1β+ macrophages – a particular type of immune cell – as a new possible target with which to improve the efficacy of the immunotherapy.
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Reprogrammed macrophages
Macrophages are cells of the innate immune system that are responsible for eliminating microorganisms, destroying infected cells, and promoting inflammation to fight pathogens and other external threats. However, tumors are able to reprogram many components of our immune system and make them work in their favor. And macrophages are among the cells that undergo this transformation: when present in abundance in the tumor microenvironment, these “tumor-associated macrophages” (or TAMs) result in a greater likelihood of resistance to treatments, a higher risk of metastasis, and the lower patient survival.
It is therefore a very promising target for the development of new immunotherapies, but in the case of pancreatic ductal adenocarcinoma, the most widespread type of pancreatic cancer, the heterogeneity of Tams and the complexity of their interaction with the tumor microenvironment have made it difficult to exploit these cells for therapeutic purposes until now. The San Raffaele study, supported by the Airc Foundation for cancer research, the European Research Council and the Ministry of Health, overcame the problem by using new innovative single cell and spatial transcriptomic technologies, capable of revealing the molecular characteristics of thousands of individual cells in their natural microenvironment. And he thus identified a subgroup of macrophages, called IL-1β+ TAMs, which seem capable of stimulating the aggressiveness of tumor cells in their vicinity.
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A vicious inflammatory cycle
“In addition to being characterized by a compromised immune system that limits the effectiveness of even the most advanced immunotherapies, pancreatic cancer has a strong inflammatory component – specific Renato Ostunihead of the Genomics of the Innate Immune System laboratory at the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and associate professor at the Vita-Salute San Raffaele University who led the research – This is particularly relevant since the onset of tissue damage – and the resulting inflammatory responses, such as pancreatitis – are known risk factors for neoplastic development”.
The IL-1β+ Tam identified by the Ostuni group could be the key to clarifying the mechanisms involved in this abnormal inflammatory response. Once reprogrammed by the tumor, in fact, these macrophages perform a double harmful function: they promote inflammation of the tissues surrounding the tumor and release molecules that induce the development and activation of other IL-1β+ Tams.
“It is a sort of self-sustaining vicious circle – underlines Ostuni – The macrophages make the tumor cells more aggressive, and the tumor cells reprogram the macrophages capable of promoting inflammation and the progression of the disease”. The study also highlighted how these “crazy” cells are localized near the inflamed tumor cells, within small niches from which, with their action, they support the progression of the disease.
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The next steps
The experiments of the San Raffaele researchers, carried out for now in vitro (i.e. only on cells), have shown that by interfering with this inflammatory loop it is possible to slow the growth of pancreatic tumor cells and reduce their inflammation. For this reason, IL-1β+ Tam could prove to be extremely interesting candidates for the development of new therapeutic strategies with which to increase the effectiveness of immunotherapies, or to study preventive strategies to interfere with the onset of the disease in people at risk. It will take years of work to imagine clinical applications of this discovery, but it is an extremely promising line of research. The Universities of Turin and Verona, the French Institute for Health and Medical Research (Inserm), the Biopolis research center in Singapore and the University of Shanghai also collaborated in the study.