Lung cancer, identified mechanism of resistance to immunotherapy

2023-09-05 13:19:23

A new mechanism of resistance to immunotherapy in lung cancer has been identified by researchers from the Regina Elena National Cancer Institute (Ire) in Rome. The discovery – the results of which are published in the ‘Journal for immunotherapy of cancer’ – could make it possible to identify patients who are more likely to respond to immunotherapy and pave the way for new effective combined therapies for others.

In lung cancer – explains a note from the Ire – the hMENA protein can exist in two variants: one has an anti-invasive action, the other on the contrary favors tumor progression. The results of the study demonstrate that the lower expression of the ‘good’ variant of hMENA, anti-invasive, activates signals in the tumor cell that mimic the presence of a virus. The latter, in turn, stimulate the production of type I interferon, one of the major antiviral cytokines with anti-tumor effects. However, when Interferon is continuously produced, it causes a paradoxical effect that can increase the aggressiveness of neoplastic cells and create a tumor microenvironment favorable to resistance to immunotherapy.

The study, supported by the Airc Foundation for cancer research – reports the IRE – was conducted by Paola Trono, now a researcher at the National Research Council (Cnr), and by Annalisa Tocci in the Immunology and Immunotherapy Unit of the IRE directed by Paola Nisticò. It was also supported by the Alliance against cancer, and saw the participation of the Ircss San Raffaele Hospital of Milan and the Irccs Humanitas Clinical Institute as well as Ifo. In Italy – recalls the note – lung cancer is the second most frequent neoplasm in men and the third in women. There were around 41,000 new diagnoses in 2020. In recent years, important advances have been recorded for this type of tumor both in early diagnosis and in molecular treatments and immunotherapy. Immune checkpoint inhibitors have revolutionized the treatment options for this neoplasm, even if the response is effective only in a percentage of patients. Hence the need to understand the mechanisms of resistance to these treatments, to better select patients more likely to respond and to identify new effective combined therapies for the others.

“A few years ago – explains Paola Nisticò – our research group had demonstrated that the hMENA protein produces different protein forms. In its various forms, the protein regulates the cytoskeleton, that complex of mostly protein filaments which constitute the scaffolding of the cell, controlling its shape and functions.Two variants of hMENA are, in particular, involved in the progression of non-small cell lung cancer with opposite functions.Therefore one has been named anti-invasive hMENA, while the other is termed pro-invasive hMENA Patients who do not have the anti-invasive version of hMENA are at increased risk of relapse and as such may be candidates for targeted post-surgical therapy.”

“In the latest study we understood – says Paola Trono – that anti-invasive hMENA in the tumor cell activates a viral sensor. As a result, various inflammatory mediators are produced that can be immunosuppressive”. “In fact – explains Annalisa Tocci – we have experimentally demonstrated that only tumor cells lacking this protein variant communicate with macrophages, cells of the immune system involved in inflammation mechanisms. In turn, macrophages respond to tumor cells, making them more aggressive”.

“All the experimental data obtained – concludes Paola Nisticò – were validated in tumor tissues of patients with lung cancer treated with immune checkpoint inhibitors. We demonstrated that factors such as the expression of anti-invasive hMENA, the interferon of type I and the presence of macrophages may represent a new frontier in precision medicine for selecting patients to be treated with immunotherapy. The data obtained in our series have been validated, with computational methods, with other large series of patients”. “The published results – comments Gennaro Ciliberto, Scientific Director of the Regina Elena Institute – are a further example of the value of translational research and of the importance of close collaboration with cancer patients and their precious biological material for a better understanding of the mechanisms underlying the disease”.