期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-34724-5
关键词
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资金
- NIH/NCI [1R01CA135328, 5R01CA227025]
- Department of Defense [W81XWH-21-1-0202]
- Prostate Cancer Foundation (PCF) grant [17CHAL06]
- Hamacher Family Prostate Cancer Research fund
- Phi Beta Psi Sorority grant
- Department of Defense award [W81XWH-21-1-0203]
- Dept. of Veterans Affairs Merit [BX002292]
- NIH [R35 GM119437, R01 AI164424, I01 BX002292, P30GM133893]
- DOE Office of Science by Brookhaven National Laboratory [DE-SC0012704]
- DOE [KP1605010]
This study identifies a T-cell pathway that leads to the inactivation of tumor-infiltrating T cells and resistance to immune therapy, thus explaining the limited effectiveness of immune checkpoint blockade (ICB) in solid tumors. Activation of the oncogenic tyrosine kinase ACK1 enhances the function of CSK, a negative regulator of T-cell activation, and constrains the activation of T cells. Inhibition of ACK1 effectively suppresses ICB-resistant tumors, providing new insights into ICB resistance mechanisms and potential targets for expanding ICB therapy.
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. 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.
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