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PD-1 expression conditions T cell avidity within an antigen-specific repertoire

Despite its negative regulatory role on tumor-specific T cells, Programmed cell death 1 (PD-1) is also a marker of activated tumor-infiltrating T cells. In cancer, PD-1 blockade partially reverses T cell dysfunction allowing the amplification of tumor reactive T cells. Here, we investigated the role...

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Autores principales: Simon, Sylvain, Vignard, Virginie, Florenceau, Laetitia, Dreno, B., Khammari, A., Lang, F., Labarriere, N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760290/
https://www.ncbi.nlm.nih.gov/pubmed/26942093
http://dx.doi.org/10.1080/2162402X.2015.1104448
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author Simon, Sylvain
Vignard, Virginie
Florenceau, Laetitia
Dreno, B.
Khammari, A.
Lang, F.
Labarriere, N.
author_facet Simon, Sylvain
Vignard, Virginie
Florenceau, Laetitia
Dreno, B.
Khammari, A.
Lang, F.
Labarriere, N.
author_sort Simon, Sylvain
collection PubMed
description Despite its negative regulatory role on tumor-specific T cells, Programmed cell death 1 (PD-1) is also a marker of activated tumor-infiltrating T cells. In cancer, PD-1 blockade partially reverses T cell dysfunction allowing the amplification of tumor reactive T cells. Here, we investigated the role of PD-1 signaling on effector/memory human T cells specific for shared melanoma antigens, derived from blood. We documented for the first time the existence of melanoma-specific T cell clones unable to express PD-1. This stable feature was due to the persistent methylation of the PDCD1 promoter. These PD-1(neg) clones were of lower avidity than their PD-1(pos) counterparts, suggesting that high-affinity-specific T cell clones unable to express PD-1 are not or rarely present in peripheral blood, as they are probably eliminated by negative selection, due to their high reactivity. We also documented the existence of such PD-1(neg) T cell clones in melanoma tumor-infiltrating lymphocytes (TIL), which also exhibited a lower functional avidity than PD-1(pos) TIL clones. This clearly shows that PD-1 expression identifies antigen-specific T cell clonotypes of high functional avidity. Finally, we demonstrated that PD-1 blockade during the in vitro selection process of Melan-A-specific T cells favored the amplification of higher avidity T cell clonotypes. This preferential amplification of high-avidity memory T cells upon PD-1 blockade resonates with the expansion of reactive T cells, including neo-antigen-specific T cells observed in anti-PD-1-treated patients. This feature should also be a useful biomarker of clinical efficiency, while providing new insights for adoptive transfer treatments.
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spelling pubmed-47602902016-03-03 PD-1 expression conditions T cell avidity within an antigen-specific repertoire Simon, Sylvain Vignard, Virginie Florenceau, Laetitia Dreno, B. Khammari, A. Lang, F. Labarriere, N. Oncoimmunology Original Research Despite its negative regulatory role on tumor-specific T cells, Programmed cell death 1 (PD-1) is also a marker of activated tumor-infiltrating T cells. In cancer, PD-1 blockade partially reverses T cell dysfunction allowing the amplification of tumor reactive T cells. Here, we investigated the role of PD-1 signaling on effector/memory human T cells specific for shared melanoma antigens, derived from blood. We documented for the first time the existence of melanoma-specific T cell clones unable to express PD-1. This stable feature was due to the persistent methylation of the PDCD1 promoter. These PD-1(neg) clones were of lower avidity than their PD-1(pos) counterparts, suggesting that high-affinity-specific T cell clones unable to express PD-1 are not or rarely present in peripheral blood, as they are probably eliminated by negative selection, due to their high reactivity. We also documented the existence of such PD-1(neg) T cell clones in melanoma tumor-infiltrating lymphocytes (TIL), which also exhibited a lower functional avidity than PD-1(pos) TIL clones. This clearly shows that PD-1 expression identifies antigen-specific T cell clonotypes of high functional avidity. Finally, we demonstrated that PD-1 blockade during the in vitro selection process of Melan-A-specific T cells favored the amplification of higher avidity T cell clonotypes. This preferential amplification of high-avidity memory T cells upon PD-1 blockade resonates with the expansion of reactive T cells, including neo-antigen-specific T cells observed in anti-PD-1-treated patients. This feature should also be a useful biomarker of clinical efficiency, while providing new insights for adoptive transfer treatments. Taylor & Francis 2015-10-29 /pmc/articles/PMC4760290/ /pubmed/26942093 http://dx.doi.org/10.1080/2162402X.2015.1104448 Text en © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License http://creativecommons.org/licenses/by-nc/3.0/, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.
spellingShingle Original Research
Simon, Sylvain
Vignard, Virginie
Florenceau, Laetitia
Dreno, B.
Khammari, A.
Lang, F.
Labarriere, N.
PD-1 expression conditions T cell avidity within an antigen-specific repertoire
title PD-1 expression conditions T cell avidity within an antigen-specific repertoire
title_full PD-1 expression conditions T cell avidity within an antigen-specific repertoire
title_fullStr PD-1 expression conditions T cell avidity within an antigen-specific repertoire
title_full_unstemmed PD-1 expression conditions T cell avidity within an antigen-specific repertoire
title_short PD-1 expression conditions T cell avidity within an antigen-specific repertoire
title_sort pd-1 expression conditions t cell avidity within an antigen-specific repertoire
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760290/
https://www.ncbi.nlm.nih.gov/pubmed/26942093
http://dx.doi.org/10.1080/2162402X.2015.1104448
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