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Harnessing αβ T cell receptor mechanobiology to achieve the promise of immuno-oncology

T cell receptors (TCR) on cytolytic T lymphocytes (CTLs) recognize "foreign" antigens bound in the groove of major histocompatibility complex (MHC) molecules (H-2 in mouse and HLA in human) displayed on altered cells. These antigens are peptide fragments of proteins derived either from inf...

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Autores principales: Reinherz, Ellis L., Hwang, Wonmuk, Lang, Matthew J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10318960/
https://www.ncbi.nlm.nih.gov/pubmed/37339184
http://dx.doi.org/10.1073/pnas.2215694120
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author Reinherz, Ellis L.
Hwang, Wonmuk
Lang, Matthew J.
author_facet Reinherz, Ellis L.
Hwang, Wonmuk
Lang, Matthew J.
author_sort Reinherz, Ellis L.
collection PubMed
description T cell receptors (TCR) on cytolytic T lymphocytes (CTLs) recognize "foreign" antigens bound in the groove of major histocompatibility complex (MHC) molecules (H-2 in mouse and HLA in human) displayed on altered cells. These antigens are peptide fragments of proteins derived either from infectious pathogens or cellular transformations during cancer evolution. The conjoint ligand formed by the foreign peptide and MHC, termed pMHC, marks an aberrant cell as a target for CTL-mediated destruction. Recent data have provided compelling evidence that adaptive protection is achieved in a facile manner during immune surveillance when mechanical load consequent to cellular motion is applied to the bond formed between an αβ TCR and its pMHC ligand arrayed on a disease-altered cell. Mechanobiology maximizes both TCR specificity and sensitivity in comparison to receptor ligation in the absence of force. While the field of immunotherapy has made advances to impact the survival of cancer patients, the latest information relevant to T cell targeting and mechanotransduction has yet to be applied for T cell monitoring and treatment of patients in the clinic. Here we review these data, and challenge scientists and physicians to apply critical biophysical parameters of TCR mechanobiology to the medical oncology field, broadening treatment success within and among various cancer types. We assert that TCRs with digital ligand-sensing performance capability directed at sparsely as well as luminously displayed tumor-specific neoantigens and certain tumor-associated antigens can improve effective cancer vaccine development and immunotherapy paradigms.
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spelling pubmed-103189602023-07-05 Harnessing αβ T cell receptor mechanobiology to achieve the promise of immuno-oncology Reinherz, Ellis L. Hwang, Wonmuk Lang, Matthew J. Proc Natl Acad Sci U S A Perspective T cell receptors (TCR) on cytolytic T lymphocytes (CTLs) recognize "foreign" antigens bound in the groove of major histocompatibility complex (MHC) molecules (H-2 in mouse and HLA in human) displayed on altered cells. These antigens are peptide fragments of proteins derived either from infectious pathogens or cellular transformations during cancer evolution. The conjoint ligand formed by the foreign peptide and MHC, termed pMHC, marks an aberrant cell as a target for CTL-mediated destruction. Recent data have provided compelling evidence that adaptive protection is achieved in a facile manner during immune surveillance when mechanical load consequent to cellular motion is applied to the bond formed between an αβ TCR and its pMHC ligand arrayed on a disease-altered cell. Mechanobiology maximizes both TCR specificity and sensitivity in comparison to receptor ligation in the absence of force. While the field of immunotherapy has made advances to impact the survival of cancer patients, the latest information relevant to T cell targeting and mechanotransduction has yet to be applied for T cell monitoring and treatment of patients in the clinic. Here we review these data, and challenge scientists and physicians to apply critical biophysical parameters of TCR mechanobiology to the medical oncology field, broadening treatment success within and among various cancer types. We assert that TCRs with digital ligand-sensing performance capability directed at sparsely as well as luminously displayed tumor-specific neoantigens and certain tumor-associated antigens can improve effective cancer vaccine development and immunotherapy paradigms. National Academy of Sciences 2023-06-20 2023-07-04 /pmc/articles/PMC10318960/ /pubmed/37339184 http://dx.doi.org/10.1073/pnas.2215694120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Perspective
Reinherz, Ellis L.
Hwang, Wonmuk
Lang, Matthew J.
Harnessing αβ T cell receptor mechanobiology to achieve the promise of immuno-oncology
title Harnessing αβ T cell receptor mechanobiology to achieve the promise of immuno-oncology
title_full Harnessing αβ T cell receptor mechanobiology to achieve the promise of immuno-oncology
title_fullStr Harnessing αβ T cell receptor mechanobiology to achieve the promise of immuno-oncology
title_full_unstemmed Harnessing αβ T cell receptor mechanobiology to achieve the promise of immuno-oncology
title_short Harnessing αβ T cell receptor mechanobiology to achieve the promise of immuno-oncology
title_sort harnessing αβ t cell receptor mechanobiology to achieve the promise of immuno-oncology
topic Perspective
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10318960/
https://www.ncbi.nlm.nih.gov/pubmed/37339184
http://dx.doi.org/10.1073/pnas.2215694120
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