Yuta Myojin, Sepideh Babaei, Rajiv Trehan, Christoph Hoffman, Noemi Kedei, Benjamin Ruf, Mohamed-Reda Benmebarek, Kylynda C Bauer, Patrick Huang, Chi Ma, Cecilia Monge, Changqing Xie, Donna Hrones, Austin G Duffy, Paul Armstrong, Lorenz Kocheise, Fiona Desmond, Jemma Buchalter, Marie Galligan, Colin Cantwell, Ronan Ryan, Jeff McCann, Michele Bourke, Ross Mac Nicholas, Ray McDermott, Joy Awosika, Maggie Cam, Rosanna Krebs, Anuradha Budhu, Mahler Revsine, William D Figg, David E Kleiner, Bernadette Redd, Bradford J Wood, Xin Wei Wang, Firouzeh Korangy, Manfred Claassen, Tim F Greten
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引用次数: 0
摘要
背景：肝细胞癌（HCC）是癌症相关死亡的主要原因。tremelimumab和durvalumab的联合治疗现在是晚期HCC的标准治疗选择。目的：研究tremelimumab和durvalumab治疗HCC患者的免疫应答。设计：我们用durvalumab、tremelimumab和局部治疗治疗28例HCC患者。我们对患者血液和肿瘤样本进行了高维多组学分析，包括全外显子组测序、单细胞RNA测序、CO-Detection by indEXing、流式细胞术和多种细胞因子/趋化因子分析，并整合这些数据来阐明免疫相关性和反应机制。用抗pd - l1 +抗ctla4治疗同基因肝癌小鼠，对肝淋巴细胞、肿瘤浸润淋巴细胞和外周血单核细胞进行分析。结果：中位总生存期为19.2个月。肿瘤组织分析显示干扰素反应增强，对应答者有更强的作用。基因组变异分析显示应答者抗原呈递增强。空间分析显示，无应答性肿瘤的treg数量更多，位于富含免疫细胞的街区，表达更高水平的ICOS和PD-1。相反，在这些富含treg的社区中，无应答的PD1+CD8+T表达较低的ICOS。细胞通讯分析表明，Treg-CD8+T相互作用在无应答组织中增强。外周血分析显示应答者经典单核细胞增多，无应答者Tregs增多。在临床前模型中证实Treg-CD8+T相互作用。最后，对860个特征进行全跨分析的单例计算分析，从而确定包括Treg特征在内的多组学特征集。结论：我们的研究为深入分析免疫治疗研究中的免疫相关因素提供了蓝图，并证明了Treg分布在HCC中的重要性。试验注册号：NCT02821754，草案标识符：2019-002767-98。
Multiomics analysis of immune correlatives in hepatocellular carcinoma patients treated with tremelimumab plus durvalumab.
Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. The combination of tremelimumab and durvalumab is now a standard treatment option for advanced HCC.
Objective: To study immune responses in HCC patients treated with tremelimumab and durvalumab.
Design: We treated 28 HCC patients with durvalumab, tremelimumab and locoregional therapies. We performed a high-dimensional multiomics analysis including whole exome sequencing, single-cell RNA seq, CO-Detection by indEXing, flow cytometry and multiplex cytokine/chemokine analysis of patients' blood and tumour samples and integrated this data to elucidate immune correlatives and response mechanisms. Mice with syngeneic HCC were treated with anti-PD-L1 plus anti-CTLA4 for hepatic lymphocytes, tumour-infiltrating lymphocytes and peripheral blood mononuclear cell analysis.
Results: The median overall survival was 19.2 months. Tumour tissue analysis revealed enhanced interferon responses, with stronger effects in responders. Gene set variation analysis indicated enhanced antigen presentation in responders. Spatial analysis revealed that non-responder tumours had higher numbers of Tregs located in neighbourhoods enriched with immune cells and expressed higher levels of ICOS and PD-1. Conversely, non-responder PD1+CD8+T in these Treg-enriched neighbourhoods expressed lower ICOS. Cell-communication analysis demonstrated that Treg-CD8+T interaction was enhanced in non-responder tissue. Peripheral blood analysis showed increased classical monocytes in responders and Tregs in non-responders. Treg-CD8+T interaction was confirmed in preclinical models. Finally, single-patient computational analysis from the all-across analysis was performed on 860 features, which led to the identification of multiomics feature sets including Treg features.
Conclusion: Our study provides a blueprint for in-depth analysis of immune correlates in immunotherapy studies and demonstrates the importance of Treg distribution in HCC.
Trial registration numbers: NCT02821754 and the EudraCT identifier: 2019-002767-98.
期刊介绍：
Gut is a renowned international journal specializing in gastroenterology and hepatology, known for its high-quality clinical research covering the alimentary tract, liver, biliary tree, and pancreas. It offers authoritative and current coverage across all aspects of gastroenterology and hepatology, featuring articles on emerging disease mechanisms and innovative diagnostic and therapeutic approaches authored by leading experts.
As the flagship journal of BMJ's gastroenterology portfolio, Gut is accompanied by two companion journals: Frontline Gastroenterology, focusing on education and practice-oriented papers, and BMJ Open Gastroenterology for open access original research.
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