PO.IM02.02 · 免疫学
FAK与PYK2对MHC-II抗原呈递的相反调控:对治疗干预的意义
Opposing control of MHC-II antigen presentation by FAK and PYK2: Implications for therapeutic intervention
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
高级别浆液性卵巢癌(HGSOC)是美国最致命的妇科恶性肿瘤,以对化疗和免疫治疗的耐药为特征。尽管黏着斑激酶(FAK和PYK2)已知可诱导肿瘤微环境免疫抑制,但其在改变肿瘤细胞主要组织相容性复合体II类(MHC-II)呈递方面的作用尚需进一步研究。HGSOC肿瘤突变较少,但常表现出FAK扩增(约75%)。值得注意的是,MHC-II表达升高与复发性HGSOC中更长的无进展生存相关,可能通过增强CD4⁺T细胞激活和改善抗肿瘤免疫实现。流式细胞术分析显示,以ATP竞争性小分子抑制FAK激酶活性(FAKi)可在体外和体内增加MHC-II抗原呈递。用FAK蛋白降解靶向嵌合体(FAK-PROTAC)处理后进行的靶向FAK蛋白降解产生了类似效果。在同基因原位小鼠模型中,FAK耗竭诱导MHC-II达到与激酶失活FAK相当的水平,这与FAK活性缺失促进肿瘤MHC-II表达一致。由于卵巢肿瘤细胞也表达FAK相关同源物PYK2,我们采用CRISPR选择性地在人OVCAR3、小鼠KMF和小鼠HGS2卵巢肿瘤模型中失活FAK和/或PYK2表达。值得注意的是,FAK缺失(而非PYK2缺失)导致这些细胞中MHC-II呈递增强。由于用双重FAK-PYK2抑制剂或靶向FAK和PYK2的PROTAC处理肿瘤细胞并不像选择性FAK缺失那样诱导MHC-II表达,我们的结果支持PYK2在卵巢肿瘤细胞中具有独特的免疫原性作用。正在进行的研究正在评估FAK抑制时PYK2的作用机制以及CIITA(II类主要组织相容性复合体反式激活因子)转录的调控。总体而言,我们的发现提示FAK特异性抑制剂具有可能增强MHC-II相关适应性免疫应答的作用,可作为晚期卵巢癌的一种治疗策略。
查看英文原文 English abstract
High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in the U.S. and is marked by resistance to chemo- and immunotherapy. Although focal adhesion kinases (FAK and PYK2) are known to induce tumor microenvironment immunosuppression, their role in altering tumor-cell major histocompatibility complex class-II (MHC-II) presentation requires further investigation. HGSOC tumors have few mutations but frequently show FAK amplification (~75%). Notably, elevated MHC-II expression correlates with longer progression-free survival in recurrent HGSOC, likely through enhanced CD4⁺ T-cell activation and improved anti-tumor immunity. Flow cytometry analysis revealed that ATP competitive small molecule inhibition of FAK kinase activity (FAKi) increases MHC-II antigen presentation in vitro and in vivo . Targeted FAK protein degradation following treatment with a FAK proteolysis targeting chimera (FAK-PROTAC) produced a similar effect. In a syngeneic orthotopic mouse model, FAK depletion induced MHC-II to levels comparable to kinase-dead FAK, consistent with the loss of FAK activity in promoting tumor MHC-II expression. As ovarian tumor cells also express the FAK-related homolog PYK2, CRISPR was employed to selectively inactivate FAK and or PYK2 expression in human OVCAR3, murine KMF, and murine HGS2 ovarian tumor models. Notably, loss of FAK, but not PYK2, resulted in enhanced MHC-II presentation in these cells. As tumor cell treatment with a dual FAK-PYK2 inhibitor or PROTAC that targets FAK and PYK2 does not induce MHC-II expression as does selective loss of FAK, our results support a distinct immunogenic role for PYK2 in ovarian tumor cells. Ongoing studies are evaluating PYK2 mechanism of action upon FAK inhibition and the regulation of CIITA (class II, major histocompatibility complex, transactivator) transcription. Collectively, our findings suggest roles for FAK-specific inhibitors that may potentiate MHC-II-related adaptive immune responses as a therapeutic strategy for advanced ovarian cancer.
利益披露 Disclosure
T. J. Haanen, None..
X. Chen, None..
D. D. Schlaepfer, None.