Pancreatic cancer, here’s how to neutralize the obstacles to the immune response. « Medicine in the Library

Pancreatic cancer is one of the most resistant to immunotherapy: a study, coordinated by Iov – Veneto Oncological Institute and the University of Verona, traces a new path to try to overcome this resistance, modifying the tumor microenvironment.

The researchers analyzed a mechanism of evasion from the immunological control implemented by pancreatic cancer by integrating functional, phenotypic and molecular data and developed a combined immunotherapy approach, effective in preclinical models in which the human immune system has been reconstituted.

In patients with pancreatic cancer, the neutrophils, cells of the immune system circulating in the blood, are activated by factors produced by the neoplastic cells and release, spontaneously and in an uncontrolled way, complex molecular structures, called NET. These structures, which resemble a real network, are mainly made up of genetic material (DNA) and proteins. Among the latter, the enzyme arginase 1 (ARG1) it is activated within the NETs, ​​generating some molecular forms that cause the excessive consumption of an amino acid essential to the anti-tumor activity of T lymphocytes: the immune response towards the tumor is, in fact, hindered.

To counteract the functional blockage of T lymphocytes, the study group generated a new antibody capable of recognizing and neutralizing the human ARG1 enzyme. Through functional and biochemical assays, it has been shown that T lymphocyte function is restored with the antibody mAb 1.10while chemical inhibitors of the enzyme are not effective in blocking the molecular forms activated in cancer patients.

In humanized preclinical models of pancreatic cancer, the administration of mAb 1.10 increases the efficacy of immunotherapy based both on the use of immunological checkpoint inhibitors and on the transfer of cytotoxic lymphocytes specific for the tumor antigen telomerase. These data were also confirmed on pancreatic tumor biopsies exposed in vitro to the anti-ARG1 antibody.

Read the full text of the article:
Neutralization of NET-associated human ARG1 enhances cancer immunotherapy
BY STEFANIA CANÈ, ROZA MARIA BAROUNI, MARINA FABBI, JOHN CUOZZO, GIULIO FRACASSO, ANNALISA ADAMO, STEFANO UGEL, ROSALINDA TROVATO, FRANCESCO DE SANCTIS, MAURO GIACCA[…] VINCENZO BRONTE.
SCIENCE TRANSLATIONAL MEDICINE 15 Mar 2023 Vol 15, Issue 687 DOI: 10.1126/scitranslmed.abq6221

Source: Iov – Veneto Oncological Institute