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Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

We have recently described that DNA-damage inducing drug DTIC, administered before peptide (Melan-A and gp100)-vaccination, improves anti-tumor CD8(+) Melan-A-specific T-cell functionality, enlarges the Melan-A(+) TCR repertoire and impacts the overall survival of melanoma patients. To identify whet...

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Autores principales: Palermo, Belinda, Franzese, Ornella, Donna, Cosmo Di, Panetta, Mariangela, Quintarelli, Concetta, Sperduti, Isabella, Gualtieri, Novella, Foddai, Maria Laura, Proietti, Enrico, Ferraresi, Virginia, Ciliberto, Gennaro, Nisticò, Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279427/
https://www.ncbi.nlm.nih.gov/pubmed/30524882
http://dx.doi.org/10.1080/2162402X.2018.1465163
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author Palermo, Belinda
Franzese, Ornella
Donna, Cosmo Di
Panetta, Mariangela
Quintarelli, Concetta
Sperduti, Isabella
Gualtieri, Novella
Foddai, Maria Laura
Proietti, Enrico
Ferraresi, Virginia
Ciliberto, Gennaro
Nisticò, Paola
author_facet Palermo, Belinda
Franzese, Ornella
Donna, Cosmo Di
Panetta, Mariangela
Quintarelli, Concetta
Sperduti, Isabella
Gualtieri, Novella
Foddai, Maria Laura
Proietti, Enrico
Ferraresi, Virginia
Ciliberto, Gennaro
Nisticò, Paola
author_sort Palermo, Belinda
collection PubMed
description We have recently described that DNA-damage inducing drug DTIC, administered before peptide (Melan-A and gp100)-vaccination, improves anti-tumor CD8(+) Melan-A-specific T-cell functionality, enlarges the Melan-A(+) TCR repertoire and impacts the overall survival of melanoma patients. To identify whether the two Ags employed in the vaccination differently shape the anti-tumor response, herein we have carried out a detailed analysis of phenotype, anti-tumor functionality and TCR repertoire in treatment-driven gp100-specific CD8(+) T cells, in the same patients previously analyzed for Melan-A. We found that T-cell clones isolated from patients treated with vaccination alone possessed an Early/intermediate differentiated phenotype, whereas T cells isolated after DTIC plus vaccination were late-differentiated. Sequencing analysis of the TCRBV chains of 29 treatment-driven gp100-specific CD8(+) T-cell clones revealed an oligoclonal TCR repertoire irrespective of the treatment schedule. The high anti-tumor activity observed in T cells isolated after chemo-immunotherapy was associated with low PD-1 expression. Differently, T-cell clones isolated after peptide-vaccination alone expressed a high level of PD-1, along with LAG-3 and TIM-3, and were neither tumor-reactive nor polyfunctional. Blockade of PD-1 reversed gp100-specific CD8(+) T-cell dysfunctionality, confirming the direct role of this co-inhibitory molecule in suppressing anti-tumor activity, differently from what we have previously observed for Melan-A(+)CD8(+) T cells, expressing PD-1 but highly functional. These findings indicate that the functional advantage induced by combined chemo-immunotherapy is determined by the tumor antigen nature, T-cell immune-checkpoints phenotype, TCR repertoire diversity and anti-tumor T-cell quality and highlights the importance of integrating these parameters to develop effective immunotherapeutic strategies.
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spelling pubmed-62794272018-12-06 Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients Palermo, Belinda Franzese, Ornella Donna, Cosmo Di Panetta, Mariangela Quintarelli, Concetta Sperduti, Isabella Gualtieri, Novella Foddai, Maria Laura Proietti, Enrico Ferraresi, Virginia Ciliberto, Gennaro Nisticò, Paola Oncoimmunology Original Research We have recently described that DNA-damage inducing drug DTIC, administered before peptide (Melan-A and gp100)-vaccination, improves anti-tumor CD8(+) Melan-A-specific T-cell functionality, enlarges the Melan-A(+) TCR repertoire and impacts the overall survival of melanoma patients. To identify whether the two Ags employed in the vaccination differently shape the anti-tumor response, herein we have carried out a detailed analysis of phenotype, anti-tumor functionality and TCR repertoire in treatment-driven gp100-specific CD8(+) T cells, in the same patients previously analyzed for Melan-A. We found that T-cell clones isolated from patients treated with vaccination alone possessed an Early/intermediate differentiated phenotype, whereas T cells isolated after DTIC plus vaccination were late-differentiated. Sequencing analysis of the TCRBV chains of 29 treatment-driven gp100-specific CD8(+) T-cell clones revealed an oligoclonal TCR repertoire irrespective of the treatment schedule. The high anti-tumor activity observed in T cells isolated after chemo-immunotherapy was associated with low PD-1 expression. Differently, T-cell clones isolated after peptide-vaccination alone expressed a high level of PD-1, along with LAG-3 and TIM-3, and were neither tumor-reactive nor polyfunctional. Blockade of PD-1 reversed gp100-specific CD8(+) T-cell dysfunctionality, confirming the direct role of this co-inhibitory molecule in suppressing anti-tumor activity, differently from what we have previously observed for Melan-A(+)CD8(+) T cells, expressing PD-1 but highly functional. These findings indicate that the functional advantage induced by combined chemo-immunotherapy is determined by the tumor antigen nature, T-cell immune-checkpoints phenotype, TCR repertoire diversity and anti-tumor T-cell quality and highlights the importance of integrating these parameters to develop effective immunotherapeutic strategies. Taylor & Francis 2018-09-11 /pmc/articles/PMC6279427/ /pubmed/30524882 http://dx.doi.org/10.1080/2162402X.2018.1465163 Text en © 2018 The Author(s). Published with license by Taylor & Francis Group, LLC. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
spellingShingle Original Research
Palermo, Belinda
Franzese, Ornella
Donna, Cosmo Di
Panetta, Mariangela
Quintarelli, Concetta
Sperduti, Isabella
Gualtieri, Novella
Foddai, Maria Laura
Proietti, Enrico
Ferraresi, Virginia
Ciliberto, Gennaro
Nisticò, Paola
Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients
title Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients
title_full Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients
title_fullStr Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients
title_full_unstemmed Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients
title_short Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients
title_sort antigen-specificity and dtic before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and tcr repertoire in melanoma patients
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279427/
https://www.ncbi.nlm.nih.gov/pubmed/30524882
http://dx.doi.org/10.1080/2162402X.2018.1465163
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