Multiomics analysis of immune correlatives in hepatocellular carcinoma patients treated with tremelimumab plus durvalumab
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Le résumé fourni par la source
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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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Multiomics analysis of immune correlatives in hepatocellular carcinoma patients treated with tremelimumab plus durvalumab
- Date Crossref
- 18/02/2025
- Éditeur
- BMJ
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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National Institutes of Health Office of Science and Technology Resources pays non établi dans la noticeOrganisme public
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National Cancer Institute Center for Cancer Research pays non établi dans la noticeOrganisme public
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Center for Cancer Research pays non établi dans la noticeStructure de recherche
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University Children's Hospital Tübingen pays non établi dans la noticeÉtablissement de santé
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University of Tübingen pays non établi dans la noticeUniversité ou école supérieure
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Office of Science pays non établi dans la noticeOrganisme public
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Mater Misericordiae University Hospital pays non établi dans la noticeÉtablissement de santé
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University College Dublin Clinical Research Centre pays non établi dans la noticeUniversité ou école supérieure
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St. Vincent's University Hospital pays non établi dans la noticeÉtablissement de santé
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University Hospital Tübingen Department of Internal Medicine I (Gastroenterology pays non établi dans la noticeUniversité ou école supérieure
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Interfaculty Institute for Biomedical Informatics (IBMI) pays non établi dans la noticeUniversité ou école supérieure
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St Vincent’s University Hospital pays non établi dans la noticeUniversité ou école supérieure
Office of Science and Technology Resources — National Institutes of Health, Center for Cancer Research — National Cancer Institute et Center for Cancer Research, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.