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- Title
Overcoming immune checkpoint blockade resistance in solid tumors with intermittent ITK inhibition.
- Authors
Zhao, Manzhi; Li, Ling; Kiernan, Caoimhe H.; Castro Eiro, Melisa D.; Dammeijer, Floris; van Meurs, Marjan; Brouwers-Haspels, Inge; Wilmsen, Merel E. P.; Grashof, Dwin G. B.; van de Werken, Harmen J. G.; Hendriks, Rudi W.; Aerts, Joachim G.; Mueller, Yvonne M.; Katsikis, Peter D.
- Abstract
Cytotoxic CD8 + T cell (CTL) exhaustion is driven by chronic antigen stimulation. Reversing CTL exhaustion with immune checkpoint blockade (ICB) has provided clinical benefits in different types of cancer. We, therefore, investigated whether modulating chronic antigen stimulation and T-cell receptor (TCR) signaling with an IL2-inducible T-cell kinase (ITK) inhibitor, could confer ICB responsiveness to ICB resistant solid tumors. In vivo intermittent treatment of 3 ICB-resistant solid tumor (melanoma, mesothelioma or pancreatic cancer) with ITK inhibitor significantly improved ICB therapy. ITK inhibition directly reinvigorate exhausted CTL in vitro as it enhanced cytokine production, decreased inhibitory receptor expression, and downregulated the transcription factor TOX. Our study demonstrates that intermittent ITK inhibition can be used to directly ameliorate CTL exhaustion and enhance immunotherapies even in solid tumors that are ICB resistant.
- Subjects
IMMUNE checkpoint proteins; PROGRAMMED cell death 1 receptors; BRAF genes; TUMORS; TRANSCRIPTION factors; PANCREATIC cancer; CD8 antigen; T cells
- Publication
Scientific Reports, 2023, Vol 13, Issue 1, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-023-42871-y