B-cell lymphomas: IOR discovery sheds light on resistance to treatment
Institutional Communication Service
The Lymphoma Genomics Laboratory, led by Prof. Francesco Bertoni at the Institute of Oncology Research (IOR), affiliated to the Università della Svizzera italiana (USI) and member of Bios⁺, has identified a potential mechanism that enables certain B-cell lymphomas to become resistant to therapy. The study was published in Blood, one of the leading scientific journals in hematology and the official journal of the American Society of Hematology. Highlighting the significance of these findings, the study was accompanied by an editorial in the same journal that emphasized its contribution to understanding the mechanisms of resistance to therapy.
In recent years, drugs such as ibrutinib have significantly improved the treatment of several blood cancers by blocking a protein called BTK, which plays a key role in the survival of tumor cells. However, in some patients, these drugs either fail to work or lose their effectiveness over time.
Until now, genetic mutations have been among the known causes of resistance, although they could not explain many cases. The new study shows that lymphoma cells can develop alternative strategies to evade treatment without altering their DNA.
The researchers discovered that some tumor cells produce high levels of interleukin-16 (IL-16), a molecule normally involved in communication between cells of the immune system. IL-16 binds to a protein called CD9 on the surface of lymphoma cells, activating a series of signaling pathways that promote tumor cell survival and reduce their sensitivity to treatment.
“In other words, when the main pathway targeted by the drugs is blocked, tumor cells can activate an alternative pathway that allows them to continue growing and surviving” said Dr. Alberto J. Arribas, co-corresponding author.
In experimental models, blocking IL-16, CD9, or one of the signaling pathways they activate can restore the tumor cells’ sensitivity to therapy. These findings suggest that the IL-16/CD9 axis could serve both as a biomarker to help identify patients at greater risk of developing resistance and as a potential new therapeutic target.
“Understanding how tumor cells manage to escape treatment is essential for developing increasingly effective therapies,” says Prof. Francesco Bertoni, Director of the Lymphoma Genomics Laboratory at IOR.
Although the findings are promising, the authors emphasize that this is preclinical research. Further studies will therefore be needed to determine whether this approach can ultimately be translated into new treatments for patients.
The discovery represents an important step forward in understanding the mechanisms of treatment resistance in B-cell lymphomas and opens new avenues for the development of more targeted and personalized therapies.
Publication details
Alberto J. Arribas, Eleonora Cannas, Giulio Sartori, Francesca Guidetti, Luciano Cascione, Sara Napoli, Gabriela Forestieri, Federica Fuzio, Emma Pesenti, Chiara Tarantelli, Filippo Spriano, Antonella Zucchetto, Francesca M. Rossi, Alessio Bruscaggin, Andrea Rinaldi, Manuel Castro de Moura, Sandra Jovic, Andrea Raimondi, Roberta Bordone Pittau, Lodovico Terzi di Bergamo, Xiaofei Ye, Anastasios Stathis, Yaacov Ben-David, Qiang Pan-Hammarström, Federico Simonetta, Georg Stussi, Emanuele Zucca, Valter Gattei, Jennifer R. Brown, Manel Esteller, Davide Rossi, Francesco Bertoni. “IL-16 production is a mechanism of resistance to BTK inhibitors and R-CHOP in lymphomas”
Blood (2026) 148 (10): 1312–1327, Link: https://doi.org/10.1182/blood.2025029956.
