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

• Published in: Nature communications Vol. 13; no. 1; pp. 6929 - 21
• Main Authors: Sridaran, Dhivya, Chouhan, Surbhi, Mahajan, Kiran, Renganathan, Arun, Weimholt, Cody, Bhagwat, Shambhavi, Reimers, Melissa, Kim, Eric H., Thakur, Manish K., Saeed, Muhammad A., Pachynski, Russell K., Seeliger, Markus A., Miller, W. Todd, Feng, Felix Y., Mahajan, Nupam P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-11-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 631/337/458/1733; 631/67/1059/2325; 631/67/580/1884; 64/60; 692/4028/67/589/466; 82/1; 82/58; 82/80; 82/83; 96/21; 96/31; 96/95; 96/98; Animals; Castration; CD4 antigen; CD8 antigen; Cdc42 protein; Cell activation; CSK Tyrosine-Protein Kinase; Effector cells; Enzymatic activity; Humanities and Social Sciences; Humans; Immune checkpoint; Immune Checkpoint Inhibitors; Kinases; Lymphocytes; Lymphocytes T; Male; Mice; multidisciplinary; Phosphorylation; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Protein-tyrosine kinase; Protein-Tyrosine Kinases - metabolism; Science; Science & Technology - Other Topics; Science (multidisciplinary); Signal transduction; Solid tumors; Therapy; Tumors; Tyrosine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34724-5

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.
Immune checkpoint blockade is showing promise in cancer immune therapy, but many solid tumours are resistant. Authors here identify a pathway in T cells that leads to increased activity of C-terminal Src kinase, a negative regulator of T cell activity, thus disabling tumour infiltrating T cells and causing immune therapy resistance.