Predictive biomarkers of immunotherapy response with pharmacological applications in solid tumors.


Journal

Acta pharmacologica Sinica
ISSN: 1745-7254
Titre abrégé: Acta Pharmacol Sin
Pays: United States
ID NLM: 100956087

Informations de publication

Date de publication:
Sep 2023
Historique:
received: 06 11 2022
accepted: 14 03 2023
medline: 31 8 2023
pubmed: 14 4 2023
entrez: 13 4 2023
Statut: ppublish

Résumé

Immune-checkpoint inhibitors show promising effects in the treatment of multiple tumor types. Biomarkers are biological indicators used to select patients for a systemic anticancer treatment, but there are only a few clinically useful biomarkers such as PD-L1 expression and tumor mutational burden, which can be used to predict immunotherapy response. In this study, we established a database consisting of both gene expression and clinical data to identify biomarkers of response to anti-PD-1, anti-PD-L1, and anti-CTLA-4 immunotherapies. A GEO screening was executed to identify datasets with simultaneously available clinical response and transcriptomic data regardless of cancer type. The screening was restricted to the studies involving administration of anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, durvalumab) or anti-CTLA-4 (ipilimumab) agents. Receiver operating characteristic (ROC) analysis and Mann-Whitney test were executed across all genes to identify features related to therapy response. The database consisted of 1434 tumor tissue samples from 19 datasets with esophageal, gastric, head and neck, lung, and urothelial cancers, plus melanoma. The strongest druggable gene candidates linked to anti-PD-1 resistance were SPIN1 (AUC = 0.682, P = 9.1E-12), SRC (AUC = 0.667, P = 5.9E-10), SETD7 (AUC = 0.663, P = 1.0E-09), FGFR3 (AUC = 0.657, P = 3.7E-09), YAP1 (AUC = 0.655, P = 6.0E-09), TEAD3 (AUC = 0.649, P = 4.1E-08) and BCL2 (AUC = 0.634, P = 9.7E-08). In the anti-CTLA-4 treatment cohort, BLCAP (AUC = 0.735, P = 2.1E-06) was the most promising gene candidate. No therapeutically relevant target was found to be predictive in the anti-PD-L1 cohort. In the anti-PD-1 group, we were able to confirm the significant correlation with survival for the mismatch-repair genes MLH1 and MSH6. A web platform for further analysis and validation of new biomarker candidates was set up and available at https://www.rocplot.com/immune . In summary, a database and a web platform were established to investigate biomarkers of immunotherapy response in a large cohort of solid tumor samples. Our results could help to identify new patient cohorts eligible for immunotherapy.

Identifiants

pubmed: 37055532
doi: 10.1038/s41401-023-01079-6
pii: 10.1038/s41401-023-01079-6
pmc: PMC10462766
doi:

Substances chimiques

Ipilimumab 0
Biomarkers, Tumor 0
SETD7 protein, human EC 2.1.1.43
Histone-Lysine N-Methyltransferase EC 2.1.1.43

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

1879-1889

Informations de copyright

© 2023. The Author(s).

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Auteurs

Szonja Anna Kovács (SA)

Department of Bioinformatics, Semmelweis University, Tűzoltó utca 7-9, 1094, Budapest, Hungary.
Doctoral School of Pathological Sciences, Semmelweis University, Üllői út 26, 1085, Budapest, Hungary.
National Laboratory for Drug Research and Development, Magyar tudósok körútja 2 1117, Budapest, Hungary.

János Tibor Fekete (JT)

National Laboratory for Drug Research and Development, Magyar tudósok körútja 2 1117, Budapest, Hungary.
Research Centre for Natural Sciences, Oncology Biomarker Research Group, Institute of Enzymology, Eötvös Loránd Research Network, Magyar Tudósok körútja 2, 1117, Budapest, Hungary.

Balázs Győrffy (B)

Department of Bioinformatics, Semmelweis University, Tűzoltó utca 7-9, 1094, Budapest, Hungary. gyorffy.balazs@med.semmelweis-univ.hu.
Department of Pediatrics, Semmelweis University, Tűzoltó utca 7-9, 1094, Budapest, Hungary. gyorffy.balazs@med.semmelweis-univ.hu.

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