PO.ET09.05 · 实验与分子治疗
PI3Kdelta的实体瘤细胞内在功能
Solid tumor cell-intrinsic function of PI3Kdelta
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
PI3Kdelta是一种主要富集于白细胞的I类PI3K，由p110delta催化亚基（由PIK3CD编码）和最常见的p85alpha调节亚基（由PIK3R1编码）组成。PI3Kdelta是B细胞功能的重要调节因子，一直是针对B细胞恶性肿瘤的广泛药物开发的靶点，已有多种抑制剂被批准用于该适应症。基于我们的临床前研究，PI3Kdelta抑制现在也正作为实体瘤的一种免疫治疗方法出现。调节性T细胞（Treg）对PI3Kdelta抑制极为敏感，因此药理学PI3Kdelta抑制剂优先靶向Treg，使免疫系统重新平衡以有利于效应T细胞介导的抗肿瘤免疫应答。这一概念目前正在葡萄膜黑色素瘤和非小细胞肺癌的临床试验中进行研究。值得注意的是，我们和其他研究者还观察到包括胶质母细胞瘤、黑色素瘤、乳腺癌、前列腺癌、神经母细胞瘤和肝细胞癌在内的多种实体瘤类型也表达野生型PIK3CD，其表达水平往往远高于其非转化的起源细胞类型。一些研究提示PI3Kdelta促进这些肿瘤细胞的增殖，但这一点仍不明确，存在抑制剂使用浓度超出PI3Kdelta特异性范围的可能，且这些发现未通过遗传学方法得到一致证实。这引出了如下问题：PI3Kdelta在实体瘤中发挥何种功能，以及将PI3Kdelta抑制剂用于免疫治疗时，如何通过抑制细胞内在PI3Kdelta而影响肿瘤细胞本身。使用高度选择性的PI3Kdelta抑制剂和CRISPR-Cas9介导的实体瘤细胞系PIK3CD缺失，我们证明PI3Kdelta抑制在这些模型中不影响细胞增殖。然而，通过体外和异种移植研究，我们鉴定了PI3Kdelta在实体瘤中与癌症相关的作用，其意义将予以介绍。我们的数据表明，在制定PI3Kdelta靶向免疫治疗研究方案时，应考虑实体瘤细胞内在的PI3Kdelta表达。
查看英文原文 English abstract
PI3Kdelta is a predominantly leukocyte-enriched class I PI3K consisting of the p110delta catalytic subunit (encoded by PIK3CD ) and most commonly the p85alpha regulatory subunit (encoded by PIK3R1 ). PI3Kdelta is an important regulator of B-cell function and has been the target of extensive drug development efforts for B-cell malignancies, with multiple inhibitors approved for this indication. Based on our pre-clinical studies, PI3Kdelta inhibition is now also emerging as an immunotherapy approach for solid tumours. Regulatory T-cells (Treg) are exquisitely sensitive to PI3Kdelta inhibition, therefore pharmacological PI3Kdelta inhibitors preferentially target the Tregs, rebalancing the immune system in favour of an effector T cell-mediated anti-tumour immune response. This concept is currently under investigation in clinical trials in uveal melanoma and non-small cell lung cancer. Notably, we and others have also observed multiple solid tumour types including glioblastoma, melanoma, breast cancer, prostate cancer, neuroblastoma and hepatocellular carcinoma also express wild-type PIK3CD , often at much higher levels than their non-transformed cell types of origin. Some studies suggest PI3Kdelta promotes proliferation in these tumour cells, but this remains unclear with the potential that inhibitors were used at non-PI3Kdelta-specific concentrations, and these findings are not consistently confirmed with genetic approaches. This raises the questions of what function PI3Kdelta plays in solid tumours and how the use of PI3Kdelta inhibitors for immunotherapy will affect the tumour cells themselves via inhibition of cell-intrinsic PI3Kdelta. Using highly-selective PI3Kdelta inhibitors and CRISPR-Cas9-mediated PIK3CD deletion in solid tumour cell lines, we demonstrate that PI3Kdelta inhibition does not affect cell proliferation in these models. However, through both in vitro and xenograft studies, we have identified cancer-relevant roles for PI3Kdelta in solid tumours, the implications of which will be presented. Our data suggest the solid tumour cell-intrinsic PI3Kdelta expression should be considered to inform PI3Kdelta-targeting immunotherapy studies.
利益披露 Disclosure
S. E. Conduit, None..
E. Lopez-Guadamillas, None..
D. Morelli, None..
H. Howard, None..
W. Pearce, None..
C. Scudamore, None.