Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma

Background & aims: single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the mole...

Descripción completa

Detalles Bibliográficos
Autores: Haber, Philipp K., Puigvehí, Marc, Llovet, Josep Maria
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2023
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/55779
Acceso en línea:http://hdl.handle.net/10230/55779
http://dx.doi.org/10.1053/j.gastro.2022.09.005
Access Level:acceso abierto
Palabra clave:Biomarkers
Hepatocellular Carcinoma
Immunotherapy
Predictors of response
id ES_500f6d4bb08c9dcd2fb918cae170747e
oai_identifier_str oai:repositori.upf.edu:10230/55779
network_acronym_str ES
network_name_str España
repository_id_str
spelling Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinomaHaber, Philipp K.Puigvehí, MarcLlovet, Josep MariaBiomarkersHepatocellular CarcinomaImmunotherapyPredictors of responseBackground & aims: single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. Methods: overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. Results: among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. Conclusion: interferon signaling and major histocompatibility complex-related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.Elsevier202320232023info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/55779http://dx.doi.org/10.1053/j.gastro.2022.09.005reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglés© Elsevier http://dx.doi.org/10.1053/j.gastro.2022.09.005info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/557792026-06-12T07:21:37Z
dc.title.none.fl_str_mv Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma
title Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma
spellingShingle Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma
Haber, Philipp K.
Biomarkers
Hepatocellular Carcinoma
Immunotherapy
Predictors of response
title_short Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma
title_full Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma
title_fullStr Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma
title_full_unstemmed Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma
title_sort Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma
dc.creator.none.fl_str_mv Haber, Philipp K.
Puigvehí, Marc
Llovet, Josep Maria
author Haber, Philipp K.
author_facet Haber, Philipp K.
Puigvehí, Marc
Llovet, Josep Maria
author_role author
author2 Puigvehí, Marc
Llovet, Josep Maria
author2_role author
author
dc.subject.none.fl_str_mv Biomarkers
Hepatocellular Carcinoma
Immunotherapy
Predictors of response
topic Biomarkers
Hepatocellular Carcinoma
Immunotherapy
Predictors of response
description Background & aims: single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. Methods: overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. Results: among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. Conclusion: interferon signaling and major histocompatibility complex-related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/55779
http://dx.doi.org/10.1053/j.gastro.2022.09.005
url http://hdl.handle.net/10230/55779
http://dx.doi.org/10.1053/j.gastro.2022.09.005
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv © Elsevier http://dx.doi.org/10.1053/j.gastro.2022.09.005
info:eu-repo/semantics/openAccess
rights_invalid_str_mv © Elsevier http://dx.doi.org/10.1053/j.gastro.2022.09.005
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869407858614861824
score 15,812429

Similares en LA Referencia