IL-16 production is a mechanism of resistance to BTK inhibitors and R-CHOP in lymphomas
Abstract
Resistance to Bruton tyrosine kinase (BTK) inhibitors remains a major clinical challenge in B-cell lymphomas and often occurs in the absence of BTK or PLCG2 mutations. Here, we investigated non-genetic mechanisms of ibrutinib resistance in marginal zone lymphoma (MZL) and their broader therapeutic implications. Chronic ibrutinib exposure generated a resistant MZL model that showed cross-resistance to BTK inhibitors and degraders, without evidence of multidrug resistance or genetic alterations. Integrated transcriptomic, epigenetic, and proteomic analyses revealed extensive reprogramming, including activation of PI3K/AKT, MAPK, and MYC pathways, repression of apoptosis and oxidative phosphorylation, and a prominent cytokine-secretory phenotype. Interleukin-16 (IL-16) emerged as a central mediator of resistance. IL-16 was transcriptionally upregulated, actively secreted, and sufficient to induce ibrutinib resistance across multiple CD9-positive models of MZL, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), and activated B-cell-like diffuse large B-cell lymphoma. Serum IL-16 levels were elevated in ibrutinib-refractory CLL patients without BTK/PLCG2 mutations. Mechanistically, IL-16 engaged CD9-enriched membrane microdomains to activate PI3Kδ, thereby sustaining AKT and ERK signaling, stabilizing MYC, inducing NF-κB-dependent programs, and upregulating antiapoptotic effectors, including BFL1 (BCL2A1). Pharmacological or genetic disruption of the IL-16/CD9/PI3K axis restored sensitivity to BTK inhibitors and R-CHOP and abrogated IL-16-induced signaling in primary CLL samples. In conclusion, an IL-16/CD9-driven, epigenetically regulated survival pathway represents one possible mechanism of resistance to BTK inhibitors and chemoimmunotherapy, supporting therapeutic targeting of this axis in refractory B-cell lymphomas.
Article Details
Authors (32)
Alberto J Arribas
Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland
Eleonora Cannas
1 Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland, Bellinzona, Switzerland
Giulio Sartori
Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland
Francesca Guidetti
Università della Svizzera italiana, Istituto Oncologico di Ricerca
Luciano Cascione
IOR - Institute of Oncology Research, Bellinzona, Switzerland
Sara Napoli
Institute of Oncology Research, Bellinzona, Switzerland
Gabriela Forestieri
Institute of Oncology Research, Bellinzona, Switzerland
Federica Fuzio
Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland
Emma Daniela Susanna Pesenti
Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland
Chiara Tarantelli
Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland
Filippo Spriano
Institute of Oncology Research, Faculty of Biomedical Sciences, USI, bellinzona, Switzerland
Antonella Zucchetto
3Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
Francesca Maria Rossi
Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
Alessio Bruscaggin
Institute of Oncology Research, Bellinzona, Switzerland
Andrea Rinaldi
Manuel Castro de Moura
Josep Carreras Leukaemia Research Institute, Badalona, Spain
Sandra Jovic
Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
Andrea Raimondi
Protein Folding and Quality Control, Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Università della Svizzera italiana
Roberta Bordone Pittau
IOSI Oncology Institute of Southern Switzerland
Lodovico Terzi di Bergamo
Institute of Oncology Research, Bellinzona, Switzerland
Xiaofei Ye
Anastasios Stathis
Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzoona, Switzerland
Yaacov Ben-David
State Key Laboratory for Functions and Applications of Medicinal Plants, Guiyang, China
Qiang Pan-Hammarström
Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institute
Federico Simonetta
Geneva University Hospitals and University of Geneva, Genève, Switzerland
Georg Stussi
Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
Emanuele Zucca
Institute of Oncology Research, Bellinzona, Switzerland
Valter Gattei
3Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy
Jennifer R. Brown
Manel Esteller
Davide Rossi
Institute of Oncology Research, Bellinzona, Switzerland
Francesco Bertoni
Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland