DC Field | Value | Language |
---|---|---|
dc.contributor.author | Chuah, Samuel | ko |
dc.contributor.author | Lee, Joycelyn | ko |
dc.contributor.author | Song, Yuan | ko |
dc.contributor.author | Kim, Hyung-Don | ko |
dc.contributor.author | Wasser, Martin | ko |
dc.contributor.author | Kaya, Neslihan A. | ko |
dc.contributor.author | Bang, Kyunghye | ko |
dc.contributor.author | Lee, Yong Joon | ko |
dc.contributor.author | Jeon, Seung Hyuck | ko |
dc.contributor.author | Suthen, Sheena | ko |
dc.contributor.author | A'Azman, Shamirah | ko |
dc.contributor.author | Gien, Gerald | ko |
dc.contributor.author | Lim, Chun Jye | ko |
dc.contributor.author | Chua, Camillus | ko |
dc.contributor.author | Hazirah, Sharifah Nur | ko |
dc.contributor.author | Lee, Hong Kai | ko |
dc.contributor.author | Lim, Jia Qi | ko |
dc.contributor.author | Lim, Tony K. H. | ko |
dc.contributor.author | Yeong, Joe | ko |
dc.contributor.author | Chen, Jinmiao | ko |
dc.contributor.author | Shin, Eui-Cheol | ko |
dc.contributor.author | Albani, Salvatore | ko |
dc.contributor.author | Zhai, Weiwei | ko |
dc.contributor.author | Yoo, Changhoon | ko |
dc.contributor.author | Liu, Haiyan | ko |
dc.contributor.author | Choo, Su Pin | ko |
dc.contributor.author | Tai, David | ko |
dc.contributor.author | Chew, Valerie | ko |
dc.date.accessioned | 2022-12-04T02:01:31Z | - |
dc.date.available | 2022-12-04T02:01:31Z | - |
dc.date.created | 2022-12-04 | - |
dc.date.created | 2022-12-04 | - |
dc.date.issued | 2022-09 | - |
dc.identifier.citation | JOURNAL OF HEPATOLOGY, v.77, no.3, pp.683 - 694 | - |
dc.identifier.issn | 0168-8278 | - |
dc.identifier.uri | http://hdl.handle.net/10203/301554 | - |
dc.description.abstract | Background & Aims: While immune checkpoint blockade (ICB) has shown promise in patients with hepatocellular carcinoma (HCC), it is associated with modest response rates and immune -related adverse events (irAEs) are common. In this study, we aimed to decipher immune trajectories and mechanisms of response and/or irAEs in patients with HCC receiving anti -programmed cell death 1 (anti-PD-1) therapy.Methods: Pre-and on-treatment peripheral blood samples (n = 60) obtained from 32 patients with HCC (Singapore cohort) were ana-lysed by cytometry by time-of -flight and single-cell RNA sequencing, with flow cytometric validation in an independent Korean cohort (n = 29). Mechanistic validation was conducted by bulk RNA sequencing of 20 pre-and on-treatment tumour biopsies and using a murine HCC model treated with different immuno-therapeutic combinations. Results: Single-cell analyses identified CXCR3+CD8+ effector memory T (TEM) cells and CD11c+ antigen-presenting cells (APC) as associated with response (p = 0.0004 and 0.0255, respec-tively), progression-free survival (p = 0.00079 and 0.0015, respectively), and irAEs (p = 0.0034 and 0.0125, respectively) in anti-PD-1-treated patients with HCC. Type-1 conventional den-dritic cells were identified as the specific APC associated with response, while 2 immunosuppressive CD14+ myeloid clusters were linked to reduced irAEs. Further analyses of CXCR3+CD8+ TEM cells showed cell-cell interactions specific to response vs. irAEs, from which the anti-PD-1 and anti-TNFR2 combination was harnessed to uncouple these effects, resulting in enhanced response without increased irAEs in a murine HCC model.Conclusions: This study identifies early predictors of clinical response to anti-PD-1 ICB in patients with HCC and offers mechanistic insights into the immune trajectories of these im-mune subsets at the interface between response and toxicity. We also propose a new combination immunotherapy for HCC to enhance response without exacerbating irAEs.Clinical trial number: NCT03695952.Lay summary: Response rates to immune checkpoint blockade (ICB) treatment in hepatocellular carcinoma (HCC) remain modest and adverse events are common. Herein, we identified early predictors of response and gained an in-depth understanding of the immunological mechanisms behind response and adverse events in patients with HCC treated with ICB. We also proposed a new combination immunotherapy for HCC that enhances response without exacerbating adverse events.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of Euro-pean Association for the Study of the Liver. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). | - |
dc.language | English | - |
dc.publisher | ELSEVIER | - |
dc.title | Uncoupling immune trajectories of response and adverse events from anti-PD-1 immunotherapy in hepatocellular carcinoma | - |
dc.type | Article | - |
dc.identifier.wosid | 000885326300013 | - |
dc.identifier.scopusid | 2-s2.0-85130515493 | - |
dc.type.rims | ART | - |
dc.citation.volume | 77 | - |
dc.citation.issue | 3 | - |
dc.citation.beginningpage | 683 | - |
dc.citation.endingpage | 694 | - |
dc.citation.publicationname | JOURNAL OF HEPATOLOGY | - |
dc.identifier.doi | 10.1016/j.jhep.2022.03.039 | - |
dc.contributor.localauthor | Shin, Eui-Cheol | - |
dc.contributor.nonIdAuthor | Chuah, Samuel | - |
dc.contributor.nonIdAuthor | Lee, Joycelyn | - |
dc.contributor.nonIdAuthor | Song, Yuan | - |
dc.contributor.nonIdAuthor | Kim, Hyung-Don | - |
dc.contributor.nonIdAuthor | Wasser, Martin | - |
dc.contributor.nonIdAuthor | Kaya, Neslihan A. | - |
dc.contributor.nonIdAuthor | Bang, Kyunghye | - |
dc.contributor.nonIdAuthor | Suthen, Sheena | - |
dc.contributor.nonIdAuthor | A'Azman, Shamirah | - |
dc.contributor.nonIdAuthor | Gien, Gerald | - |
dc.contributor.nonIdAuthor | Lim, Chun Jye | - |
dc.contributor.nonIdAuthor | Chua, Camillus | - |
dc.contributor.nonIdAuthor | Hazirah, Sharifah Nur | - |
dc.contributor.nonIdAuthor | Lee, Hong Kai | - |
dc.contributor.nonIdAuthor | Lim, Jia Qi | - |
dc.contributor.nonIdAuthor | Lim, Tony K. H. | - |
dc.contributor.nonIdAuthor | Yeong, Joe | - |
dc.contributor.nonIdAuthor | Chen, Jinmiao | - |
dc.contributor.nonIdAuthor | Albani, Salvatore | - |
dc.contributor.nonIdAuthor | Zhai, Weiwei | - |
dc.contributor.nonIdAuthor | Yoo, Changhoon | - |
dc.contributor.nonIdAuthor | Liu, Haiyan | - |
dc.contributor.nonIdAuthor | Choo, Su Pin | - |
dc.contributor.nonIdAuthor | Tai, David | - |
dc.contributor.nonIdAuthor | Chew, Valerie | - |
dc.description.isOpenAccess | N | - |
dc.type.journalArticle | Article | - |
dc.subject.keywordAuthor | Checkpoint inhibitor | - |
dc.subject.keywordAuthor | immunoprofiling | - |
dc.subject.keywordAuthor | immune network | - |
dc.subject.keywordAuthor | cellular cross-talk | - |
dc.subject.keywordAuthor | liver cancer | - |
dc.subject.keywordPlus | T-CELLS | - |
dc.subject.keywordPlus | TUMOR | - |
dc.subject.keywordPlus | TNFR2 | - |
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