通过间歇性的ITK抑制克服实体肿瘤中的免疫检查点阻断抵抗。
Overcoming immune checkpoint blockade resistance in solid tumors with intermittent ITK inhibition.
发表日期：2023 Sep 21
作者：
Manzhi Zhao, Ling Li, Caoimhe H Kiernan, Melisa D Castro Eiro, Floris Dammeijer, Marjan van Meurs, Inge Brouwers-Haspels, Merel E P Wilmsen, Dwin G B Grashof, Harmen J G van de Werken, Rudi W Hendriks, Joachim G Aerts, Yvonne M Mueller, Peter D Katsikis
来源：
CYTOKINE & GROWTH FACTOR REVIEWS
摘要：
细胞毒性CD8+T细胞（CTL）的耗竭是由于持续抗原刺激所致。通过免疫检查点阻断（ICB）逆转CTL的耗竭已在不同类型的癌症中提供了临床益处。因此，我们研究了通过调节慢性抗原刺激和T细胞受体（TCR）信号传导，使用一种IL-2可诱导T细胞激酶（ITK）抑制剂是否能赋予ICB难治性实体肿瘤对ICB的响应能力。通过体内间歇性治疗三种ICB难治性实体瘤（黑色素瘤、间皮瘤或胰腺癌）的ITK抑制剂，显著改善了ICB治疗效果。ITK抑制可直接在体外激活耗竭的CTL，因为它增强了细胞因子的产生，减少了抑制性受体的表达，并下调了转录因子TOX的表达。我们的研究表明，间歇性ITK抑制可以直接改善CTL的耗竭并增强免疫治疗，即使在ICB难治性固体肿瘤中也同样适用。© 2023. Springer Nature Limited.
Cytotoxic CD8 + T cell (CTL) exhaustion is driven by chronic antigen stimulation. Reversing CTL exhaustion with immune checkpoint blockade (ICB) has provided clinical benefits in different types of cancer. We, therefore, investigated whether modulating chronic antigen stimulation and T-cell receptor (TCR) signaling with an IL2-inducible T-cell kinase (ITK) inhibitor, could confer ICB responsiveness to ICB resistant solid tumors. In vivo intermittent treatment of 3 ICB-resistant solid tumor (melanoma, mesothelioma or pancreatic cancer) with ITK inhibitor significantly improved ICB therapy. ITK inhibition directly reinvigorate exhausted CTL in vitro as it enhanced cytokine production, decreased inhibitory receptor expression, and downregulated the transcription factor TOX. Our study demonstrates that intermittent ITK inhibition can be used to directly ameliorate CTL exhaustion and enhance immunotherapies even in solid tumors that are ICB resistant.© 2023. Springer Nature Limited.