Dataset Information

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

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 pY18 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Prostate Epithelium

DISEASE(S): Prostate Cancer

SUBMITTER: John Koomen

LAB HEAD: Nupam Mahajan, PhD

PROVIDER: PXD037546 | Pride | 2023-03-11

REPOSITORIES: Pride

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			Action	DRS
	C4-2B_AcK1_run1.raw	Raw
	C4-2B_AcK1_run1.raw__F003326_.dta	Raw
	C4-2B_AcK1_run1.raw__F003326_.mzid.gz	Mzid
	C4-2B_AcK1_run1.raw__F003326_.mzid_C4-2B_AcK1_run1.raw__F003326_.MGF	Mzid
	C4-2B_AcK1_run2.raw	Raw

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

Sridaran Dhivya D Chouhan Surbhi S Mahajan Kiran K Renganathan Arun A Weimholt Cody C Bhagwat Shambhavi S Reimers Melissa M Kim Eric H EH Thakur Manish K MK Saeed Muhammad A MA Pachynski Russell K RK Seeliger Markus A MA Miller W Todd WT Feng Felix Y FY Mahajan Nupam P NP

Nature communications 20221114 1

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 activati ...[more]

PMID: 36376335

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