Interpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapy
AuthorsAntunes, Dinler A.
Rigo, Mauricio M.
Freitas, Martiela V.
Mendes, Marcus F. A.
Kavraki, Lydia E.
Selin, Liisa K.
Vieira, Gustavo F.
UMass Chan AffiliationsSelin Lab, Department of Pathology
Immunoprophylaxis and Therapy
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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.
Front Immunol. 2017 Oct 4;8:1210. doi: 10.3389/fimmu.2017.01210. eCollection 2017. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/40489
RightsCopyright: © 2017 Antunes, Rigo, Freitas, Mendes, Sinigaglia, Lizée, Kavraki, Selin, Cornberg and Vieira. 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 Copyright: © 2017 Antunes, Rigo, Freitas, Mendes, Sinigaglia, Lizée, Kavraki, Selin, Cornberg and Vieira. 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.