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Multiomics analysis of immune correlatives in hepatocellular carcinoma patients treated with tremelimumab plus durvalumab

银耳霉素 杜瓦卢马布 医学 肝细胞癌 免疫学 免疫系统 CD8型 免疫疗法 癌症研究 肿瘤科 无容量 易普利姆玛
作者
Yuta Myojin,Sepideh Babaei,Rajiv Trehan,Caitlin Hoffman,Noémi Kedei,Benjamin Ruf,Mohamed-Reda Benmebarek,Kylynda C. Bauer,Patrick Huang,Chi Ma,Cecilia Monge,Changqing Xie,Donna Mabry Hrones,Austin G. Duffy,Paul Armstrong,Lorenz Kocheise,Fiona Desmond,Jemma Buchalter,Marie Galligan,Colin P. Cantwell
出处
期刊:Gut [BMJ]
卷期号:: gutjnl-334026 被引量:1
标识
DOI:10.1136/gutjnl-2024-334026
摘要

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.
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