Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance

Dhivya Sridaran, Surbhi Chouhan, Kiran Mahajan, Arun Renganathan, Cody Weimholt, Shambhavi Bhagwat, Melissa Reimers, Eric H. Kim, Manish K. Thakur, Muhammad A. Saeed, Russell K. Pachynski, Markus A. Seeliger, W. Todd Miller, Felix Y. Feng and Nupam P. Mahajan ()
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Dhivya Sridaran: Washington University at St Louis
Surbhi Chouhan: Washington University at St Louis
Kiran Mahajan: Washington University at St Louis
Arun Renganathan: Washington University at St Louis
Cody Weimholt: Washington University at St Louis
Shambhavi Bhagwat: Washington University at St Louis
Melissa Reimers: Washington University at St Louis
Eric H. Kim: Washington University at St Louis
Manish K. Thakur: Stony Brook University
Muhammad A. Saeed: Washington University at St Louis
Russell K. Pachynski: Washington University at St Louis
Markus A. Seeliger: Stony Brook University
W. Todd Miller: Stony Brook University
Felix Y. Feng: University of California
Nupam P. Mahajan: Washington University at St Louis

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: Abstract Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK Y18-phosphorylation and spontaneous activation of CD8+ and CD4+ T cells, resulting in inhibited growth of transplanted ICB-resistant tumours. Furthermore, ICB treatment of castration-resistant prostate cancer (CRPC) patients results in re-activation of ACK1/pY18-CSK signalling, confirming the involvement of this pathway in ICB insensitivity. An ACK1 small-molecule inhibitor, (R)-9b, recapitulates inhibition of ICB-resistant tumours, which provides evidence for ACK1 enzymatic activity playing a pivotal role in generating ICB resistance. Overall, our study identifies an important mechanism of ICB resistance and holds potential for expanding the scope of ICB therapy to tumours that are currently unresponsive.

Date: 2022
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DOI: 10.1038/s41467-022-34724-5

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