ITK inhibition improves the response to immune checkpoint blockade in solid tumors

Abstract

Abstract Cytotoxic CD8+ T cell (CTL) exhaustion is driven by persistent T cell receptor (TCR) stimulation in chronic infections and tumors. The exhausted state of T cells is characterized by impaired effector function and proliferative capacity, upregulation of multiple inhibitory receptors and altered transcriptional profiles. The phenotypic and epigenetic changes of these cells hinder effective antitumor immunity and immunotherapy. Therefore, reinvigorating exhausted T cells may provide significant clinical benefits to patients with cancer. Our approach is to reduce chronic TCR stimulation by inhibiting IL2-inducible T-cell kinase (ITK), a pivotal component of TCR signaling. In our study, we found that intermittent ITK inhibitor treatment significantly improved ICB response in three immune checkpoint blockade (ICB) -resistant solid tumors (melanoma, mesothelioma or pancreatic cancer) in vivo. In vitro, we demonstrated that specific ITK inhibitor and ibrutinib, an inhibitor of Bruton’s tyrosine kinase (BTK) and ITK, directly reversed the exhaustion-related phenotypes in exhausted CTLs. The changes included enhanced cytokine production, decreased inhibitory receptor expression and changes in transcription factors. Subsequently, RNA-seq data revealed that exhaustion-related transcriptional profile of in vitro CTLs is reduced by ibrutinib treatment. Ibrutinib mediated reversal of CTL exhaustion was BTK independent. To conclude, our study demonstrates that ITK inhibition can be used to directly ameliorate CTLs exhaustion and overcomes immune checkpoint blockade resistance in solid tumors. This work was supported by the department of Immunology, KWF Grant 128371 (PDK), in part from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779295 (PDK), and by the China Scholarship Council for funding PhD fellowships (No. 201506160120 for MZ and 201906210055 for LL).