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Mutations associated with no durable clinical benefit to immune checkpoint blockade in Non-S-Cell lung cancer

2021Journal article Open access
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dc.contributor.authorZhu, Guangsheng
dc.contributor.authorRen, Dian
dc.contributor.authorLei, Xi
dc.contributor.authorShi, Ruifeng
dc.contributor.authorZhu, Shuai
dc.contributor.authorZhou, Ning
dc.contributor.authorZu, Lingling
dc.contributor.authorDe Mello, Ramon Andrade
dc.contributor.authorChen, Jun
dc.contributor.authorXU, Song
dc.date.accessioned2021-04-08T09:25:37Z
dc.date.available2021-04-08T09:25:37Z
dc.date.issued2021
dc.description.abstract(1) Background: The immune checkpoint blockade (ICB) has shown promising efficacy in non-small-cell lung cancer (NSCLC) patients with significant clinical benefits and durable responses, but the overall response rate to ICBs is only 20%. The lack of responsiveness to ICBs is currently a central problem in cancer immunotherapy. (2) Methods: Four public cohorts comprising 2986 patients with NSCLC were included in the study. We screened 158 patients with NSCLC with no durable clinical benefit (NDB) to ICBs in the Rizvi cohort and identified NDB-related gene mutations in these patients using univariate and multivariate Cox regression analyses. Programmed death-ligand 1 (PD-L1) expression, tumor mutation burden (TMB), neoantigen load, tumor-infiltrating lymphocytes, and immune-related gene expression were analyzed for identifying gene mutations. A comprehensive predictive classifier model was also built to evaluate the efficacy of ICB therapy. (3) Results: Mutations in FAT1 and KEAP1 were found to correlate with NDB in patients with NSCLC to ICBs; however, the analysis suggested that only mutation in FAT1 was valuable in predicting the efficacy of ICB therapy, and that mutation in KEAP1 acted as a prognostic but not a predictive biomarker for NSCLC. Mutations in FAT1 were associated with a higher TMB and lower multiple lymphocyte infiltration, including CD8 (T-Cell Surface Glycoprotein CD8)+ T cells. We established a prognostic model according to PD-L1 expression, TMB, smoking status, treatment regimen, treatment type, and FAT1 mutation, which indicated good accuracy by receiver operating characteristic (ROC) analysis (area under the curve (AUC) for 6-months survival: 0.763; AUC for 12-months survival: 0.871). (4) Conclusions: Mutation in FAT1 may be a predictive biomarker in patients with NSCLC who exhibit NDB to ICBs. We proposed an FAT1 mutation-based model for screening more suitable NSCLC patients to receive ICBs that may contribute to individualized immunotherapy.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.3390/cancers13061397pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.1/15346
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectNon-small cell lung cancerpt_PT
dc.subjectImmunotherapypt_PT
dc.subjectKEAP1pt_PT
dc.subjectFAT1pt_PT
dc.subjectPD-1/PD-L1 inhibitorspt_PT
dc.subjectAnti-PD1/PD-L1pt_PT
dc.subjectAnti-CTLA-4pt_PT
dc.subjectNo durable clinical benefitpt_PT
dc.subjectNDBpt_PT
dc.titleMutations associated with no durable clinical benefit to immune checkpoint blockade in Non-S-Cell lung cancerpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue6pt_PT
oaire.citation.startPage1397pt_PT
oaire.citation.titleCancerspt_PT
oaire.citation.volume13pt_PT
person.familyNamede Mello
person.givenNameRamon Andrade
person.identifier.orcid0000-0002-9640-4573
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication53ee625f-c5c3-468b-85bb-4cef5ad36928
relation.isAuthorOfPublication.latestForDiscovery53ee625f-c5c3-468b-85bb-4cef5ad36928

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