Overcoming immune checkpoint blockade resistance in solid tumors with intermittent ITK inhibition.

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.

• Authors: Manzhi Zhao, Ling Li, Caoimhe H Kiernan, Melisa D Castro Eiro, Floris Dammeijer, Marjan van Meurs, Inge Brouwers-Haspels, Merel E P Wilmsen, Dwin G B Grashof, Harmen J G van de Werken, Rudi W Hendriks, Joachim G Aerts, Yvonne M Mueller, Peter D Katsikis
• Journal: Scientific reports (Sci Rep) Vol. 13 Issue 1 Pg. 15678 (09 21 2023) ISSN: 2045-2322 [Electronic] England
• PMID: 37735204 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. Springer Nature Limited.

Chemical References

• emt protein-tyrosine kinase
• Immune Checkpoint Inhibitors
• Protein-Tyrosine Kinases

Topics

• Humans
• Immune Checkpoint Inhibitors
• Protein-Tyrosine Kinases
• Pancreatic Neoplasms
• Mesothelioma