PO.CL05.05 · 临床研究
鉴定放射诱导干扰素信号传导的癌细胞内在调控因子
Identifying cancer cell intrinsic regulators of radiation-induced interferon signaling
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
放射治疗(RT)诱导抗肿瘤免疫已在多种临床前模型和部分患者中观察到，并可导致持久的全身性肿瘤消退。RT对抗肿瘤免疫的调节被认为主要通过cGAS-STING激活起作用，从而引发I型干扰素(IFN)反应通路，后者协调T细胞的启动和募集以及适应性耐药(如PD-L1诱导)。个别研究已在不同背景下证明RT既有免疫激活效应也有免疫抑制效应，而这种广泛变异性的决定因素知之甚少。因此，发现不同癌细胞状态下对RT的I型IFN反应的分歧和趋同机制，可能定义增强RT驱动免疫激活的生物标志物和治疗策略。我们用2 Gy或8 Gy RT或STING激动剂DiABZI处理了100株人类癌细胞系，并进行单细胞RNA测序。我们使用IFN反应基因的复合评分以及单个IFN反应基因(包括ISG15、MX1、CXCL10和IFNB)对细胞系进行评分。随后我们选择了四株放射诱导IFN反应高的细胞系进行机制研究：两株来源于胰腺导管腺癌，两株来源于乳腺癌。我们观察到在2 Gy与8 Gy RT及DiABZI之间、以及细胞系之间，ISG15和MX1激活的动力学各不相同。值得注意的是，敲除STING消除了DiABZI反应，但在MDA-MB-231中反而矛盾地增加了放射诱导的ISG15，而在SUIT-2中则未如此。我们的研究突显了癌细胞状态之间在放射对IFN反应特征的调节上存在广泛变异性，并强调需要阐明不同癌症类型中放射诱导免疫激活和抑制的机制。
查看英文原文 English abstract
Induction of anti-tumor immunity by radiation therapy (RT) has been observed in multiple preclinical models and in selected patients and can lead to durable systemic tumor regression. Modulation of anti-tumor immunity by RT is thought to act primarily via cGAS-STING activation leading to type I interferon (IFN) response pathways, which coordinate T cell priming and recruitment and adaptive resistance such as PD-L1 induction. Individual studies have demonstrated both immune activating and immune suppressive effects of RT in various contexts, and the determinants of this wide variability are poorly understood. Discovering divergent and convergent mechanisms of type I IFN response to RT across diverse cancer cell states may thus define biomarkers and treatment strategies to enhance RT-driven immune activation. We treated 100 human cancer cell lines with 2 Gy or 8 Gy RT or the STING agonist DiABZI and performed single cell RNA sequencing. We scored cell lines using a composite of IFN response genes as well as individual IFN response genes including ISG15, MX1, CXCL10 and IFNB. We then selected four cell lines with high radiation-induced IFN response for mechanistic studies: two derived from pancreatic ductal adenocarcinoma and two from breast carcinoma. We observed distinct kinetics of ISG15 and MX1 activation between 2 Gy and 8 Gy RT and DiABZI as well as between cell lines. Notably, knockout of STING abrogated DiABZI response but paradoxically increased ISG15 induction by radiation in MDA-MB-231, but not SUIT-2. Our study highlights wide variability among cancer cell states in modulation of IFN response signatures by radiation and emphasizes the need to elucidate mechanisms of radiation-induced immune activation and suppression across diverse cancer types.
利益披露 Disclosure
O. Kaneko, None..
B. Yip, None.
A. Mehta,
Plexium g., Board of Directors, non-salaried role).
SyntheX g., Board of Directors, non-salaried role).
Monimoi g., Board of Directors, non-salaried role), Stock.
Juri Biosciences g., Board of Directors, non-salaried role).
CxT Discovery g., Board of Directors, non-salaried role).
Third Rock Ventures g., Board of Directors, non-salaried role).
Asher Biotherapeutics g., Board of Directors, non-salaried role), Stock.
Abata Therapeutics g., Board of Directors, non-salaried role), Stock.
Clasp Therapeutics g., Board of Directors, non-salaried role), Stock.
Flare Therapeutics g., Board of Directors, non-salaried role).
venBio Partners g., Board of Directors, non-salaried role).
BioNTech g., Board of Directors, non-salaried role).
Rheos Medicines g., Board of Directors, non-salaried role).
Checkmate Pharmaceuticals g., Board of Directors, non-salaried role).
The Column Group Other Business Ownership, Venture Partner.
Monet Lab Stock.
Bristol-Myers Squibb ).
N. Hacohen,
Danger Bio/Related Sciences g., Board of Directors, non-salaried role), Stock.
Repertoire Immune Medicines g., Board of Directors, non-salaried role).
CytoReason g., Board of Directors, non-salaried role).
BioNTech Stock, Patent.
Bristol-Myers Squibb ).
Moderna ).
JJDC ).
Takeda ).
Calico Life Sciences ).
R. J. Park, None.