2. Academic Validation
  3. Overcoming immune checkpoint blockade resistance in solid tumors with intermittent ITK inhibition

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

  • Sci Rep. 2023 Sep 21;13(1):15678. doi: 10.1038/s41598-023-42871-y.
Manzhi Zhao # 1 2,  Ling Li # 1,  Caoimhe H Kiernan 1,  Melisa D Castro Eiro 1,  Floris Dammeijer 3,  Marjan van Meurs 1,  Inge Brouwers-Haspels 1,  Merel E P Wilmsen 1,  Dwin G B Grashof 1,  Harmen J G van de Werken 1 4,  Rudi W Hendriks 3,  Joachim G Aerts 3,  Yvonne M Mueller 1,  Peter D Katsikis 5
Affiliations

Affiliations

  • 1 Department of Immunology, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
  • 2 Department of Pulmonary and Critical Care Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, Guangdong, China.
  • 3 Department of Pulmonary Medicine, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
  • 4 Cancer Computational Biology Center, Erasmus MC Cancer Institute, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
  • 5 Department of Immunology, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands. p.katsikis@erasmusmc.nl.
  • # Contributed equally.
PMID: 37735204 DOI: 10.1038/s41598-023-42871-y
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.

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