Interpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapy

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dc.citation.articleNumber1210en_US
dc.citation.journalTitleFrontiers in Immunologyen_US
dc.citation.volumeNumber8en_US
dc.contributor.authorAntunes, Dinler A.en_US
dc.contributor.authorRigo, Maurício M.en_US
dc.contributor.authorFreitas, Martiela V.en_US
dc.contributor.authorMendes, Marcus F.A.en_US
dc.contributor.authorSinigaglia, Marialvaen_US
dc.contributor.authorLizée, Gregoryen_US
dc.contributor.authorKavraki, Lydia E.en_US
dc.contributor.authorSelin, Liisa K.en_US
dc.contributor.authorCornberg, Markusen_US
dc.contributor.authorVieira, Gustavo F.en_US
dc.date.accessioned2017-11-15T14:12:53Zen_US
dc.date.available2017-11-15T14:12:53Zen_US
dc.date.issued2017en_US
dc.description.abstractImmunotherapy 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.en_US
dc.identifier.citationAntunes, Dinler A., Rigo, Maurício M., Freitas, Martiela V., et al.. "Interpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapy." <i>Frontiers in Immunology,</i> 8, (2017) Frontiers Media S.A.: https://doi.org/10.3389/fimmu.2017.01210.en_US
dc.identifier.digitalInterpreting_T-Cell_Cross-reactivity_through_Structureen_US
dc.identifier.doihttps://doi.org/10.3389/fimmu.2017.01210en_US
dc.identifier.urihttps://hdl.handle.net/1911/98826en_US
dc.language.isoengen_US
dc.publisherFrontiers Media S.A.en_US
dc.rightsThis 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.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subject.keywordT-cell cross-reactivityen_US
dc.subject.keywordTCR-interacting surfaceen_US
dc.subject.keywordTCR/pMHCen_US
dc.subject.keywordcancer immunotherapyen_US
dc.subject.keywordcross-reactivity hot-spotsen_US
dc.subject.keywordhierarchical clusteringen_US
dc.subject.keywordpeptide–MHC complexen_US
dc.titleInterpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapyen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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