The study published in the journal Nature by researchers at the San Raffaele hospital in Milan identifies a new potential therapeutic target to slow down the progression of pancreatic cancer
The group of scientists – under the guidance of Professor Renato Ostuni, head 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 – has discovered a new mechanism, which promotes the growth of pancreatic cancer
. This mechanism based oninteraction between IL-1β+ macrophages and some tumor cells characterized by a specific inflammatory profile and high aggressiveness. The results of the research – supported by the AIRC Foundation, the European Research Council (ERC) and the Ministry of Health – suggest that blocking this interaction could be a new strategy to counter the onset of the pancreatic cancer in people at risk or to enhance the response to immunotherapy in patients already affected by this type of cancer.
The role of macrophages
Macrophages are a type of cell of the innate immune system, essential for protecting tissue integrity and activating rapid protective responses against pathogens and other external threats. In tumors, however, the functions of macrophages are profoundly reprogrammed, to the point that these cells support the progression of the disease rather than counteract it. Tumor-associated macrophages (or TAMs) are important targets of immunotherapy, as their increased abundance is generally associated with treatment resistance, metastasis and poorer patient survival. In the case of pancreatic cancer, however, the heterogeneity of TAMs and the complexity of their interaction with the tumor microenvironment have made it difficult to target these cells for therapeutic purposes until now. In addition to being characterized by a compromised immune system which limits the effectiveness of even the most advanced immunotherapies, pancreatic cancer presents a strong inflammatory component, specifies Renato Ostuni. 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. What the ability of inflammation to promote the growth of pancreatic cancer depends on was so far unclear: with this study, researchers have identified one of the crucial mechanisms for this process.
The technologies used
To arrive at these results, the Ostuni research group used innovative single cell and spatial transcriptomic technologies, capable of revealing the molecular characteristics of thousands of individual cells in their natural microenvironment. In samples from patients with pancreatic cancer, researchers have thus identified a new subgroup of macrophages, called IL-1β+ TAM and capable of stimulate the aggressiveness of tumor cells in their vicinity. More precisely, these macrophages induce inflammatory reprogramming and promote the release of factors which, in turn, favor the development and activation of the IL-1β+ TAMs themselves. It’s sort of a self-sustaining vicious cycle. Macrophages make tumor cells more aggressive, and tumor cells reprogram macrophages capable of promoting inflammation and disease progression explains Ostuni. The study also discovered that IL-1β+ TAMs are not randomly distributed, but are localized in small niches near the inflamed tumor cells. It is precisely the physical proximity between macrophages and tumor cells that could support the progression of the disease. We conducted experiments to study how to interfere with this circuit. The results, although obtained for now only in laboratory studies, are encouraging. This approach has in fact led to a reduction in inflammation and a slowdown in the growth of pancreatic cancer, conclude Nicoletta Caronni and Francesco Vittoria, among the main authors of the article.
November 1, 2023 (changed November 1, 2023 | 5:04 pm)
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