Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Nat Commun. 2023 Mar 22;14(1):1566. doi: 10.1038/s41467-023-36878-2.
Whereas the contribution of tumor microenvironment to the profound immune suppression of glioblastoma (GBM) is clear, tumor-cell intrinsic mechanisms that regulate resistance to CD8 T cell mediated killing are less understood. Kinases are potentially druggable targets that drive tumor progression and might influence immune response. Here, we perform an in vivo CRISPR screen to identify glioma intrinsic kinases that contribute to evasion of tumor cells from CD8 T cell recognition. The screen reveals checkpoint kinase 2 (Chek2) to be the most important kinase contributing to escape from CD8 T-cell recognition. Genetic depletion or pharmacological inhibition of Chek2 with blood-brain-barrier permeable drugs that are currently being evaluated in clinical trials, in combination with PD-1 or PD-L1 blockade, lead to survival benefit in multiple preclinical glioma models. Mechanistically, loss of Chek2 enhances antigen presentation, STING pathway activation and PD-L1 expression in mouse gliomas. Analysis of human GBMs demonstrates that Chek2 expression is inversely associated with antigen presentation and T-cell activation. Collectively, these results support Chek2 as a promising target for enhancement of response to immune checkpoint blockade therapy in GBM.
虽然肿瘤微环境对胶质母细胞瘤（GBM）的深度免疫抑制作用是明确的，但肿瘤细胞内在的调节机制仍不清楚，这些机制可抵抗 CD8 T 细胞介导的杀伤。激酶是潜在的可成药靶点，可驱动肿瘤进展，并可能影响免疫反应。在这里，我们进行了体内 CRISPR 筛选，以鉴定内在的胶质瘤激酶，这些激酶有助于肿瘤细胞逃避 CD8 T 细胞的识别。该筛选揭示了检查点激酶 2（Chek2）是最重要的激酶，有助于逃避 CD8 T 细胞的识别。用目前正在临床试验中评估的血脑屏障通透性药物进行 Chek2 的基因缺失或药物抑制，与 PD-1 或 PD-L1 阻断联合使用，可使多种临床前神经胶质瘤模型获益。从机制上讲，Chek2 的缺失增强了小鼠神经胶质瘤中的抗原呈递、STING 通路激活和 PD-L1 的表达。对人 GBM 的分析表明，Chek2 的表达与抗原呈递和 T 细胞激活呈负相关。总的来说，这些结果支持 Chek2 作为增强 GBM 免疫检查点阻断治疗反应的有前途的靶点。
