Pancreatic cancer is one of the big killers of oncology: in most cases it is diagnosed late, when surgery is no longer curative, and it is often resistant to immunotherapy, one of the most powerful weapons in the oncologists’ arsenal. However, understanding what makes this tumor so refractory to the action of the immune system could pave the way for the development of new treatments and, in the future, concretely improve the lives of millions of patients around the world. And a new clue comes today from an Italian study, which on the pages of Science Translational Medicine investigated the possibility of improving the efficacy of immunotherapy against pancreatic ductal adenocarcinoma (the most common form, accounting for almost 70% of diagnoses), by specifically inhibiting the action of arginase 1, an enzyme secreted by neutrophils (cells of the immune system) within the tumor micro-environment.
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“For several years we have been trying to understand which mechanisms allow tumors to escape the action of the immune system, and one of the discoveries we have made is that arginase 1 plays an important role in the case of so-called cold tumors, those in which we find very few T lymphocytes within the tumor mass”, Vincenzo Bronte, Scientific Director of the Veneto Oncological Institute, explains to Salute. “For this reason we decided to further investigate the possibility of inhibiting the activity of this enzyme in patients with pancreatic ductal adenocarcinoma, a cold tumor that rarely responds to immunotherapy.”
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The role of arginase – continues Bronte – is to reduce the concentration of arginine, an amino acid that promotes the proliferation of T lymphocytes. The presence of arginase in the microenvironment surrounding tumors – this is the researchers’ hypothesis – “starves ” the lymphocytes, which cannot therefore correctly play their role as defenders of the organism, allowing the cancer to proliferate undisturbed and to resist the action of immunotherapies more easily.
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Traditional animal models cannot be used to study the matter further, because in mice and humans arginase is produced by different cell lines. The researchers then studied cell samples taken from patients with pancreatic cancer, identifying a modified form of neutrophils that produce a protein structure known as neutrophil extracellular traps (or Nets), inside which arginase 1 and other molecules are trapped. By studying these structures they also discovered that the arginase contained in the Nets is cut by another enzyme, transforming into an “active” form that effectively reduces the proliferation of T lymphocytes.
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A first step towards a new strategy
“Using humanized mice – says Bronte – we have demonstrated that a monoclonal antibody directed against the modified form of arginase 1 is able to block its action, increasing the quantity of T lymphocytes present within a pancreatic tumor, and enhancing the action of different classes of immunotherapies”. The monoclonal antibody used in the study is derived from rodents, and therefore cannot be used effectively in human patients. The next step will therefore be to obtain a humanised monoclonal antibody, i.e. adapted to the human organism, with which it would be possible to start human trials to verify whether its addition to an immunotherapy regimen is able to improve the chances of response in ductal adenocarcinoma of the pancreas and other forms of solid tumours