microRNA expression patterns in tumor infiltrating lymphocytes are strongly associated with response to adoptive cell transfer therapy.
Cancer Immunol Immunother
; 70(6): 1541-1555, 2021 Jun.
Article
em En
| MEDLINE
| ID: mdl-33201337
ABSTRACT
Adoptive cell transfer (ACT) using autologous tumor infiltrating lymphocytes (TILs) was previously shown to yield clinical response in metastatic melanoma patients as an advanced line. Unfortunately, there is no reliable marker for predicting who will benefit from the treatment. We analyzed TIL samples from the infusion bags used for treatment of 57 metastatic melanoma patients and compared their microRNA profiles. The discovery cohort included six responding patients and seven patients with progressive disease, as defined by RECIST1.1. High throughput analysis with NanoString nCounter demonstrated significantly higher levels of miR-34a-5p and miR-22-3p among TIL from non-responders. These results were validated in TIL infusion bag samples from an independent cohort of 44 patients, using qRT-PCR of the individual microRNAs. Using classification trees, a data-driven predictive model for response was built, based on the level of expression of these microRNAs. Patients that achieved stable disease were classified with responders, setting apart the patients with progressive disease. Moreover, the expression levels of miR-34a-5p in the infused TIL created distinct survival groups, which strongly supports its role as a potential biomarker for TIL-ACT therapy. Indeed, when tested against autologous melanoma cells, miRLow TIL cultures exhibited significantly higher cytotoxic activity than miRHigh TIL cultures, and expressed features of terminally exhausted effectors. Finally, overexpression of miR-34a-5p or miR-22-3p in TIL inhibited their cytotoxic ability in vitro. Overall, we show that a two-microRNA signature correlates with failure of TIL-ACT therapy and survival in melanoma patients.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Biomarcadores Tumorais
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Regulação Neoplásica da Expressão Gênica
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Linfócitos do Interstício Tumoral
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Transferência Adotiva
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MicroRNAs
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Melanoma
Tipo de estudo:
Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article