Baseline and post-treatment biomarkers of resistance to anti-PD-1 therapy in acral and mucosal melanoma: an observational study

BackgroundImmunotherapies targeting programmed cell death-1 (PD-1) and its ligands have improved clinical outcomes for advanced melanoma. However, many tumors exhibit primary resistance or acquire secondary resistance after an initial positive response. The mechanisms of resistance are not well unde...

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Vydané v:Journal for immunotherapy of cancer Ročník 10; číslo 7; s. e004879
Hlavní autori: Shui, Irene M., Liu, Xiao Qiao, Zhao, Qing, Kim, Seung Tae, Sun, Yuan, Yearley, Jennifer H., Choudhury, Tasmiah, Webber, Andrea L., Krepler, Clemens, Cristescu, Razvan, Lee, Jeeyun
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: England BMJ Publishing Group Ltd 01.07.2022
BMJ Publishing Group LTD
BMJ Publishing Group
Edícia:Original research
Predmet:
Antigen presentation
Apoptosis
Biomarkers
Biomarkers - analysis
Biomarkers, Tumor
Cancer
Cell death
Clinical outcomes
Gene expression
Humans
Immunotherapy
Immunotherapy Biomarkers
Kinases
Melanoma
Melanoma - immunology
Melanoma - pathology
Melanoma - therapy
Metastasis
Mutation
Observational studies
Programmed Cell Death 1 Receptor
Programmed Cell Death 1 Receptor - antagonists & inhibitors
Programmed Cell Death 1 Receptor - immunology
Retrospective Studies
RNA, Messenger - biosynthesis
Tumors
Programmed Cell Death 1 Receptor
Biomarkers, Tumor
Melanoma
ISSN:2051-1426, 2051-1426
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Shrnutí:BackgroundImmunotherapies targeting programmed cell death-1 (PD-1) and its ligands have improved clinical outcomes for advanced melanoma. However, many tumors exhibit primary resistance or acquire secondary resistance after an initial positive response. The mechanisms of resistance are not well understood, and no validated predictive biomarkers are available. This exploratory study aimed to characterize baseline differences and molecular changes arising during treatment in acral and mucosal melanomas that exhibited primary or secondary resistance to anti-PD-1 monotherapy.MethodsThis was an observational retrospective study of 124 patients who had been treated for metastatic acral or mucosal melanoma with anti-PD-1 monotherapy. Tumor samples were collected at baseline (all patients) and post-treatment (resistant tumors only) and were assayed by immunohistochemistry, whole-exome sequencing, and RNA sequencing.ResultsAt baseline, more non-progressor than resistant tumors exhibited expression of PD-L1, immune cell infiltration, and high tumor mutational burden (TMB); baseline PD-L1 expression was also more common in secondary-resistant than in primary-resistant tumors as well as in late versus early secondary-resistant tumors. Non-progressor tumors also had higher median baseline expression of an 18-gene T cell-inflamed gene expression profile (TcellinfGEP). Among resistant tumors, the proportion of PD-L1-positive melanomas and the expression of the TcellinfGEP mRNA signature increased during treatment, while the expression of mRNA signatures related to WNT and INFA1 signaling decreased. There was evidence for greater changes from baseline in secondary-resistant versus primary-resistant tumors for some markers, including expression of RAS-related and WNT-related mRNA signatures and density of CD11c+ and FOXP3+ T cells. Greater changes in CD11c+ cell density were observed in early compared with late secondary-resistant tumors.ConclusionsOur findings suggest that TcellinfGEP and PD-L1 expression, TMB, immune cell infiltration, and RAS and WNT signaling warrant further investigation as potential mechanisms and/or biomarkers of anti-PD-1 therapy resistance in acral and mucosal melanomas. Confirmation of these findings in larger populations is needed.
Bibliografia:Original research
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SourceType-Scholarly Journals-1
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ISSN:2051-1426
2051-1426
DOI:10.1136/jitc-2022-004879