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

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...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10514027/
https://www.ncbi.nlm.nih.gov/pubmed/37735204
http://dx.doi.org/10.1038/s41598-023-42871-y
Descripción
Sumario: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.