Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance.
Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance.
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DOI：
10.1038/s41467-022-34724-5
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发表时间：
2022-11-14
影响因子：
16.6
通讯作者：
Mahajan, Nupam P.
中科院分区：
文献类型：
--
作者：
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.
实体瘤对免疫检查点阻断(ICB)治疗的耐受性很高，这是由于效应器T细胞的功能受损和它们向肿瘤的低效率转运造成的。T细胞的激活受C-末端Src激酶(CSK)的负性调节，但其确切机制尚不清楚。在这里，我们发现保守的致癌酪氨酸激酶激活的CDC42激酶1(AcK1)能够在酪氨酸18(PY18)处磷酸化CSK，从而增强CSK的功能，抑制T细胞的激活。缺乏编码AcK1的TNK2基因的小鼠，其特征是CSK Y18磷酸化水平降低，CD8+和CD4+T细胞自发激活，导致移植的ICB耐药肿瘤生长受到抑制。此外，ICB对去势抵抗型前列腺癌(CRPC)患者的治疗导致AcK1/pY18-CSK信号的重新激活，证实该通路参与了ICB不敏感的过程。AcK1小分子抑制剂(R)-9b概括了对ICB耐药肿瘤的抑制作用，这为AcK1酶活性在产生ICB耐药中发挥关键作用提供了证据。总体而言，我们的研究确定了ICB耐药的一个重要机制，并有可能将ICB治疗的范围扩大到目前无反应的肿瘤。免疫检查点阻断在癌症免疫治疗中显示出希望，但许多实体肿瘤是耐药的。在这里，作者发现了T细胞中的一条途径，该途径导致C末端Src激酶活性增加，这是T细胞活性的负调节因子，从而阻止肿瘤侵袭T细胞，并导致免疫治疗抵抗。
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.
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影响因子：
13.3
作者：
Chouhan, Surbhi;Sawant, Mithila;Weimholt, Cody;Luo, Jingqin;Sprung, Robert W.;Terrado, Mailyn;Mueller, David M.;Earp, H. Shelton;Mahajan, Nupam P.
通讯作者：
Mahajan, Nupam P.
影响因子：
11.2
作者：
Harlin H;Meng Y;Peterson AC;Zha Y;Tretiakova M;Slingluff C;McKee M;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
3.7
作者：
Gajiwala KS;Maegley K;Ferre R;He YA;Yu X
通讯作者：
Yu X
影响因子：
14.8
作者：
Drost J;Karthaus WR;Gao D;Driehuis E;Sawyers CL;Chen Y;Clevers H
通讯作者：
Clevers H
影响因子：
8
作者：
Buchwald, M.;Pietschmann, K.;Brand, P.;Guenther, A.;Mahajan, N. P.;Heinzel, T.;Kraemer, O. H.
通讯作者：
Kraemer, O. H.