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
Abstract
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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