Italian Researchers Identify hMENA Protein Role in Lung Cancer Immunotherapy Resistance

Researchers at the Regina Elena National Cancer Institute (IRE) in Rome have identified a mechanism by which non-small cell lung cancer protects itself from the immune system, reducing the effectiveness of immunotherapies. The results were published in the Journal for ImmunoTherapy of Cancer.

At the heart of the research is the hMENA protein, which regulates a group of cancer-associated fibroblasts. These are non-cancerous cells, but they can make tumors more aggressive and resistant to treatment. These cells produce a particularly dense extracellular matrix, which increases tissue rigidity and limits the access of immune cells to the tumor.

The structure, reminiscent of walls and moats built around a medieval city, makes the tumor more difficult to reach and attack, even when the immune system is reactivated with immunotherapy. The cells that form this barrier also activate molecular signals, particularly the TGF-β pathway, which reduces the immune system's activity and promotes the accumulation of regulatory T cells, which in turn inhibit the immune response.

The data also highlighted a vicious cycle of mutual reinforcement between TGF-β and hMENA: each protein keeps the other active, consolidating a tumor-friendly microenvironment over time. By analyzing data from large groups of patients, the research team's bioinformaticians identified a molecular signature associated with this specific tumor microenvironment, which is associated with a worse prognosis and a reduced response to immunotherapy.

Data from the study showed that tumors do not grow in isolation, but actively shape their surrounding environment. In this context, fibroblasts surrounding the tumor, guided by the hMENA protein, help hamper the immune response and simultaneously directly influence tumor cells. Cancer cells thus acquire characteristics that make them more mobile and invasive, promoting disease progression.

Lung cancer is the third most common type in Italy, and when diagnosed at an advanced stage, the chances of cure are significantly reduced. Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of cases, is the most common form. In recent years, immunotherapy has revolutionized the treatment landscape, but not all patients respond to these innovative treatments. Even among those whose tumors are initially sensitive, resistance often develops over time.

The research group of the IRE Immunology and Immunotherapy Unit, which identified the hMENA protein several years ago, is now developing pharmacological strategies to block its cancer-promoting action and drug resistance. The goal is to overcome resistance to immunotherapy, launching a new phase of therapeutic development.

"Understanding how tumors construct their own defense system, which allows them to grow and escape the immune system's control, is one of the most important challenges in oncology today," says Paola Nisticò, head of the Immunology and Immunotherapy Unit at IRE. "The results of our study represent an important step in this direction, paving the way for new therapeutic strategies."

The scientific director of the Regina Elena Institute commented that the data help clarify one of the most complex issues in contemporary oncology: the role of the tumor environment in therapy resistance. This is an example of research that doesn't simply describe a phenomenon, but identifies new, concrete directions for making treatments more effective.

The study was supported by the AIRC Foundation for Cancer Research and is the result of a multidisciplinary collaboration integrating experimental research, immunology, and bioinformatics.