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 whether...
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doaj-68373cd86cff4bdc93b8465e055a25a62020-11-25T03:18:50ZengTaylor & Francis GroupOncoImmunology2162-402X2018-12-0171210.1080/2162402X.2018.14651631465163Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patientsBelinda Palermo0Ornella Franzese1Cosmo Di Donna2Mariangela Panetta3Concetta Quintarelli4Isabella Sperduti5Novella Gualtieri6Maria Laura Foddai7Enrico Proietti8Virginia Ferraresi9Gennaro Ciliberto10Paola Nisticò11Advanced Diagnostics and Technological Innovation, IRCCS Regina Elena National Cancer InstituteUniversity of Tor VergataAdvanced Diagnostics and Technological Innovation, IRCCS Regina Elena National Cancer InstituteAdvanced Diagnostics and Technological Innovation, IRCCS Regina Elena National Cancer InstituteIRCCS Ospedale Pediatrico Bambino GesùRegina Elena National Cancer InstituteAdvanced Diagnostics and Technological Innovation, IRCCS Regina Elena National Cancer InstituteRegina Elena National Cancer InstituteIstituto Superiore di SanitàRegina Elena National Cancer InstituteRegina Elena National Cancer InstituteAdvanced Diagnostics and Technological Innovation, IRCCS Regina Elena National Cancer InstituteWe 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.http://dx.doi.org/10.1080/2162402X.2018.1465163chemo-immunotherapydacarbazinehuman melanomagp100melan-acd8+ t cellspd-1cd28tcr diversityclonotypes |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Belinda Palermo Ornella Franzese Cosmo Di Donna Mariangela Panetta Concetta Quintarelli Isabella Sperduti Novella Gualtieri Maria Laura Foddai Enrico Proietti Virginia Ferraresi Gennaro Ciliberto Paola Nisticò |
spellingShingle |
Belinda Palermo Ornella Franzese Cosmo Di Donna Mariangela Panetta Concetta Quintarelli Isabella Sperduti Novella Gualtieri Maria Laura Foddai Enrico Proietti Virginia Ferraresi Gennaro Ciliberto Paola Nisticò Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients OncoImmunology chemo-immunotherapy dacarbazine human melanoma gp100 melan-a cd8+ t cells pd-1 cd28 tcr diversity clonotypes |
author_facet |
Belinda Palermo Ornella Franzese Cosmo Di Donna Mariangela Panetta Concetta Quintarelli Isabella Sperduti Novella Gualtieri Maria Laura Foddai Enrico Proietti Virginia Ferraresi Gennaro Ciliberto Paola Nisticò |
author_sort |
Belinda Palermo |
title |
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_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_sort |
antigen-specificity and dtic before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and tcr repertoire in melanoma patients |
publisher |
Taylor & Francis Group |
series |
OncoImmunology |
issn |
2162-402X |
publishDate |
2018-12-01 |
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. |
topic |
chemo-immunotherapy dacarbazine human melanoma gp100 melan-a cd8+ t cells pd-1 cd28 tcr diversity clonotypes |
url |
http://dx.doi.org/10.1080/2162402X.2018.1465163 |
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