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dc.contributor.authorAntunes, Dinler A.
Rigo, Maurício M.
Freitas, Martiela V.
Mendes, Marcus F.A.
Sinigaglia, Marialva
Lizée, Gregory
Kavraki, Lydia E.
Selin, Liisa K.
Cornberg, Markus
Vieira, Gustavo F.
dc.date.accessioned 2017-11-15T14:12:53Z
dc.date.available 2017-11-15T14:12:53Z
dc.date.issued 2017
dc.identifier.citation Antunes, Dinler A., Rigo, Maurício M., Freitas, Martiela V., et al.. "Interpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapy." Frontiers in Immunology, 8, (2017) Frontiers Media S.A.: https://doi.org/10.3389/fimmu.2017.01210.
dc.identifier.urihttps://hdl.handle.net/1911/98826
dc.description.abstract Immunotherapy has become one of the most promising avenues for cancer treatment, making use of the patient’s own immune system to eliminate cancer cells. Clinical trials with T-cell-based immunotherapies have shown dramatic tumor regressions, being effective in multiple cancer types and for many different patients. Unfortunately, this progress was tempered by reports of serious (even fatal) side effects. Such therapies rely on the use of cytotoxic T-cell lymphocytes, an essential part of the adaptive immune system. Cytotoxic T-cells are regularly involved in surveillance and are capable of both eliminating diseased cells and generating protective immunological memory. The specificity of a given T-cell is determined through the structural interaction between the T-cell receptor (TCR) and a peptide-loaded major histocompatibility complex (MHC); i.e., an intracellular peptide–ligand displayed at the cell surface by an MHC molecule. However, a given TCR can recognize different peptide–MHC (pMHC) complexes, which can sometimes trigger an unwanted response that is referred to as T-cell cross-reactivity. This has become a major safety issue in TCR-based immunotherapies, following reports of melanoma-specific T-cells causing cytotoxic damage to healthy tissues (e.g., heart and nervous system). T-cell cross-reactivity has been extensively studied in the context of viral immunology and tissue transplantation. Growing evidence suggests that it is largely driven by structural similarities of seemingly unrelated pMHC complexes. Here, we review recent reports about the existence of pMHC “hot-spots” for cross-reactivity and propose the existence of a TCR interaction profile (i.e., a refinement of a more general TCR footprint in which some amino acid residues are more important than others in triggering T-cell cross-reactivity). We also make use of available structural data and pMHC models to interpret previously reported cross-reactivity patterns among virus-derived peptides. Our study provides further evidence that structural analyses of pMHC complexes can be used to assess the intrinsic likelihood of cross-reactivity among peptide-targets. Furthermore, we hypothesize that some apparent inconsistencies in reported cross-reactivities, such as a preferential directionality, might also be driven by particular structural features of the targeted pMHC complex. Finally, we explain why TCR-based immunotherapy provides a special context in which meaningful T-cell cross-reactivity predictions can be made.
dc.language.iso eng
dc.publisher Frontiers Media S.A.
dc.rights This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.title Interpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapy
dc.type Journal article
dc.citation.journalTitle Frontiers in Immunology
dc.subject.keywordT-cell cross-reactivity
TCR-interacting surface
TCR/pMHC
cancer immunotherapy
cross-reactivity hot-spots
hierarchical clustering
peptide–MHC complex
dc.citation.volumeNumber 8
dc.identifier.digital Interpreting_T-Cell_Cross-reactivity_through_Structure
dc.type.dcmi Text
dc.identifier.doihttps://doi.org/10.3389/fimmu.2017.01210
dc.identifier.pmcid PMC5632759
dc.identifier.pmid 29046675
dc.type.publication publisher version
dc.citation.articleNumber 1210


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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Except where otherwise noted, this item's license is described as This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.