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Negative intracellular regulators of T-cell receptor (TCR) signaling as potential antitumor immunotherapy targets

Immunotherapy strategies aim to mobilize immune defenses against tumor cells by targeting mainly T cells. Co‐inhibitory receptors or immune checkpoints (ICPs) (such as PD-1 and CTLA4) can limit T cell receptor (TCR) signal propagation in T cells. Antibody-based blocking of immune checkpoints (immune...

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Autores principales: Laletin, Vladimir, Bernard, Pierre-Louis, Costa da Silva, Cathy, Guittard, Geoffrey, Nunes, Jacques A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10231026/
https://www.ncbi.nlm.nih.gov/pubmed/37217244
http://dx.doi.org/10.1136/jitc-2022-005845
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author Laletin, Vladimir
Bernard, Pierre-Louis
Costa da Silva, Cathy
Guittard, Geoffrey
Nunes, Jacques A
author_facet Laletin, Vladimir
Bernard, Pierre-Louis
Costa da Silva, Cathy
Guittard, Geoffrey
Nunes, Jacques A
author_sort Laletin, Vladimir
collection PubMed
description Immunotherapy strategies aim to mobilize immune defenses against tumor cells by targeting mainly T cells. Co‐inhibitory receptors or immune checkpoints (ICPs) (such as PD-1 and CTLA4) can limit T cell receptor (TCR) signal propagation in T cells. Antibody-based blocking of immune checkpoints (immune checkpoint inhibitors, ICIs) enable escape from ICP inhibition of TCR signaling. ICI therapies have significantly impacted the prognosis and survival of patients with cancer. However, many patients remain refractory to these treatments. Thus, alternative approaches for cancer immunotherapy are needed. In addition to membrane‐associated inhibitory molecules, a growing number of intracellular molecules may also serve to downregulate signaling cascades triggered by TCR engagement. These molecules are known as intracellular immune checkpoints (iICPs). Blocking the expression or the activity of these intracellular negative signaling molecules is a novel field of action to boost T cell-mediated antitumor responses. This area is rapidly expanding. Indeed, more than 30 different potential iICPs have been identified. Over the past 5 years, several phase I/II clinical trials targeting iICPs in T cells have been registered. In this study, we summarize recent preclinical and clinical data demonstrating that immunotherapies targeting T cell iICPs can mediate regression of solid tumors including (membrane associated) immune‐checkpoint inhibitor refractory cancers. Finally, we discuss how these iICPs are targeted and controlled. Thereby, iICP inhibition is a promising strategy opening new avenues for future cancer immunotherapy treatments.
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spelling pubmed-102310262023-06-01 Negative intracellular regulators of T-cell receptor (TCR) signaling as potential antitumor immunotherapy targets Laletin, Vladimir Bernard, Pierre-Louis Costa da Silva, Cathy Guittard, Geoffrey Nunes, Jacques A J Immunother Cancer Review Immunotherapy strategies aim to mobilize immune defenses against tumor cells by targeting mainly T cells. Co‐inhibitory receptors or immune checkpoints (ICPs) (such as PD-1 and CTLA4) can limit T cell receptor (TCR) signal propagation in T cells. Antibody-based blocking of immune checkpoints (immune checkpoint inhibitors, ICIs) enable escape from ICP inhibition of TCR signaling. ICI therapies have significantly impacted the prognosis and survival of patients with cancer. However, many patients remain refractory to these treatments. Thus, alternative approaches for cancer immunotherapy are needed. In addition to membrane‐associated inhibitory molecules, a growing number of intracellular molecules may also serve to downregulate signaling cascades triggered by TCR engagement. These molecules are known as intracellular immune checkpoints (iICPs). Blocking the expression or the activity of these intracellular negative signaling molecules is a novel field of action to boost T cell-mediated antitumor responses. This area is rapidly expanding. Indeed, more than 30 different potential iICPs have been identified. Over the past 5 years, several phase I/II clinical trials targeting iICPs in T cells have been registered. In this study, we summarize recent preclinical and clinical data demonstrating that immunotherapies targeting T cell iICPs can mediate regression of solid tumors including (membrane associated) immune‐checkpoint inhibitor refractory cancers. Finally, we discuss how these iICPs are targeted and controlled. Thereby, iICP inhibition is a promising strategy opening new avenues for future cancer immunotherapy treatments. BMJ Publishing Group 2023-05-22 /pmc/articles/PMC10231026/ /pubmed/37217244 http://dx.doi.org/10.1136/jitc-2022-005845 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Review
Laletin, Vladimir
Bernard, Pierre-Louis
Costa da Silva, Cathy
Guittard, Geoffrey
Nunes, Jacques A
Negative intracellular regulators of T-cell receptor (TCR) signaling as potential antitumor immunotherapy targets
title Negative intracellular regulators of T-cell receptor (TCR) signaling as potential antitumor immunotherapy targets
title_full Negative intracellular regulators of T-cell receptor (TCR) signaling as potential antitumor immunotherapy targets
title_fullStr Negative intracellular regulators of T-cell receptor (TCR) signaling as potential antitumor immunotherapy targets
title_full_unstemmed Negative intracellular regulators of T-cell receptor (TCR) signaling as potential antitumor immunotherapy targets
title_short Negative intracellular regulators of T-cell receptor (TCR) signaling as potential antitumor immunotherapy targets
title_sort negative intracellular regulators of t-cell receptor (tcr) signaling as potential antitumor immunotherapy targets
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10231026/
https://www.ncbi.nlm.nih.gov/pubmed/37217244
http://dx.doi.org/10.1136/jitc-2022-005845
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