Interleukin-2-inducible T-cell kinase inhibition to block NF-κB signaling exerts anti-tumor effects and enhances chemotherapy in NK/T-cell lymphoma

Abstract

Natural killer/T-cell lymphoma (NKTCL) is a highly aggressive non-Hodgkin lymphoma. Relapsed/refractory (R/R) NKTCL patients have dismal prognosis and lack effective treatments, novel therapeutics are urgently needed. Here we found interleukin-2-inducible T-cell kinase (ITK) expression was elevated in NKTCL cells and patient tumors. And higher ITK expression was associated with worse clinical outcomes. In vitro ITK knockdown inhibited NKTCL cell growth, induced apoptosis, cell cycle arrest and impaired its colony-forming ability while ITK overexpression accelerated cell proliferation. In vivo ITK knockdown greatly impeded lymphoma growth in mouse model, indicating it as a potential therapeutic target. Mechanistically, ITK knockdown inhibited NKTCL cell growth by attenuating oncogenic NF-κB signaling, which is revealed by transcriptomic profiling and further validated by in vitro assays and in vivo NKTCL models. Additionally, we showed that ITK inhibitors could inhibit NKTCL cell proliferation, promote apoptosis and suppressed tumor progression in NKTCL cell line-derived xenograft (CDX) model. Furthermore, we established a patient-derived xenograft (PDX) model from a NKTCL patient refractory to prior anti-PD-1 and asparaginase containing therapy. The primary cells from this patient highly expressed ITK and were responsive to ITK inhibitor. And ITK inhibitor effectively repressed tumor progression in PDX model. Finally, we found ITK inhibition improved the response of NKTCL cell lines to chemotherapy and overcome chemotherapy resistance in primary cells. Collectively, our results demonstrated that ITK served as an oncogene in NKTCL and represented a novel therapeutic vulnerability to be targeted or in combination with chemotherapy drugs for this disease.