Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
Cell Rep. 2018 Oct 2;25(1):80-94. doi: 10.1016/j.celrep.2018.09.012.
We examined hematopoietic protein kinase 1 (HPK1), whose reliance on scaffold versus kinase functions for negative immune cell regulation is poorly understood and critical to its assessment as a viable drug target. We identify kinase-dependent roles for HPK1 in CD8 T cells that restrict their anti-viral and anti-tumor responses by using HPK1 kinase-dead (HPK1.kd) knockin mice. Loss of HPK1 kinase function enhanced T cell receptor signaling and cytokine secretion in a T-cell-intrinsic manner. In response to chronic lymphocytic choriomeningitis virus (LCMV) infection or tumor challenge, viral clearance and tumor growth inhibition were enhanced in HPK1.kd mice, accompanied by an increase in effector CD8 T cell function. Co-blockade of PD-L1 further enhanced T effector cell function, resulting in superior anti-viral and anti-tumor immunity over single target blockade. These results identify the importance of HPK1 kinase activity in the negative regulation of CD8 effector functions, implicating its potential as a cancer immunotherapy target.
我们研究了造血蛋白激酶 1（HPK1），其对支架的依赖与激酶功能对于负免疫细胞调节的作用尚不清楚，这对评估其作为可行的药物靶点至关重要。我们发现 CD8 T 细胞中 HPK1 的激酶依赖性作用，通过使用 HPK1 激酶失活（HPK1.kd）敲入小鼠来限制其抗病毒和抗肿瘤反应。HPK1 激酶功能的丧失以 T 细胞内在的方式增强了 T 细胞受体信号传导和细胞因子分泌。在慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染或肿瘤挑战中，HPK1.kd 小鼠的病毒清除和肿瘤生长抑制得到增强，伴随着效应 CD8 T 细胞功能的增加。PD-L1 的共阻断进一步增强了 T 效应细胞功能，导致抗病毒和抗肿瘤免疫作用优于单一靶标阻断。这些结果表明 HPK1 激酶活性在 CD8 效应功能的负调节中的重要性，暗示其作为癌症免疫治疗靶点的潜力。
