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

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

doi:10.1038/s41598-023-42871-y

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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	15678
Journal	Scientific Reports
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41598-023-42871-y
Publication status	Published - 21 Sept 2023

Bibliographical note

Funding Information:
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). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. We thank Odilia Corneth for advice on p-ITK stains. We thank Harm de Wit for making the MHC class I tetramers and Rik Ruijten, Tessa Alofs and Tamara van Wees for technical support.

Publisher Copyright:
© 2023, Springer Nature Limited.

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Zhao, M., Li, L., Kiernan, C. H., Castro Eiro, M. D., Dammeijer, F., van Meurs, M., Brouwers-Haspels, I., Wilmsen, M. E. P., Grashof, D. G. B., van de Werken, H. J. G., Hendriks, R. W., Aerts, J. G., Mueller, Y. M., & Katsikis, P. D. (2023). Overcoming immune checkpoint blockade resistance in solid tumors with intermittent ITK inhibition. Scientific Reports, 13(1), Article 15678. https://doi.org/10.1038/s41598-023-42871-y

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title = "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.",

author = "Manzhi Zhao and Ling Li and Kiernan, {Caoimhe H.} and {Castro Eiro}, {Melisa D.} and Floris Dammeijer and {van Meurs}, Marjan and Inge Brouwers-Haspels and Wilmsen, {Merel E.P.} and Grashof, {Dwin G.B.} and {van de Werken}, {Harmen J.G.} and Hendriks, {Rudi W.} and Aerts, {Joachim G.} and Mueller, {Yvonne M.} and Katsikis, {Peter D.}",

note = "Funding Information: This work was supported by the department of Immunology, KWF Grant 128371 (PDK), in part from the European Union{\textquoteright}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). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. We thank Odilia Corneth for advice on p-ITK stains. We thank Harm de Wit for making the MHC class I tetramers and Rik Ruijten, Tessa Alofs and Tamara van Wees for technical support. Publisher Copyright: {\textcopyright} 2023, Springer Nature Limited.",

year = "2023",

month = sep,

day = "21",

doi = "10.1038/s41598-023-42871-y",

language = "English",

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Zhao, M , Li, L, Kiernan, CH, Castro Eiro, MD, Dammeijer, F , van Meurs, M , Brouwers-Haspels, I, Wilmsen, MEP, Grashof, DGB, van de Werken, HJG , Hendriks, RW , Aerts, JG , Mueller, YM & Katsikis, PD 2023, 'Overcoming immune checkpoint blockade resistance in solid tumors with intermittent ITK inhibition', Scientific Reports, vol. 13, no. 1, 15678. https://doi.org/10.1038/s41598-023-42871-y

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T1 - Overcoming immune checkpoint blockade resistance in solid tumors with intermittent ITK inhibition

AU - Zhao, Manzhi

AU - Li, Ling

AU - Kiernan, Caoimhe H.

AU - Castro Eiro, Melisa D.

AU - Dammeijer, Floris

AU - van Meurs, Marjan

AU - Brouwers-Haspels, Inge

AU - Wilmsen, Merel E.P.

AU - Grashof, Dwin G.B.

AU - van de Werken, Harmen J.G.

AU - Hendriks, Rudi W.

AU - Aerts, Joachim G.

AU - Mueller, Yvonne M.

AU - Katsikis, Peter D.

N1 - Funding Information: 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). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. We thank Odilia Corneth for advice on p-ITK stains. We thank Harm de Wit for making the MHC class I tetramers and Rik Ruijten, Tessa Alofs and Tamara van Wees for technical support. Publisher Copyright: © 2023, Springer Nature Limited.

PY - 2023/9/21

Y1 - 2023/9/21

N2 - 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.

AB - 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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U2 - 10.1038/s41598-023-42871-y

DO - 10.1038/s41598-023-42871-y

M3 - Article

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AN - SCOPUS:85171868552

SN - 2045-2322

VL - 13

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 15678

ER -

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

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