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Transient cell-in-cell formation underlies tumor relapse and resistance to immunotherapy

Despite the remarkable successes of cancer immunotherapies, the majority of patients will experience only partial response followed by relapse of resistant tumors. While treatment resistance has frequently been attributed to clonal selection and immunoediting, comparisons of paired primary and relap...

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Autores principales: Gutwillig, Amit, Santana-Magal, Nadine, Farhat-Younis, Leen, Rasoulouniriana, Diana, Madi, Asaf, Luxenburg, Chen, Cohen, Jonathan, Padmanabhan, Krishnanand, Shomron, Noam, Shapira, Guy, Gleiberman, Annette, Parikh, Roma, Levy, Carmit, Feinmesser, Meora, Hershkovitz, Dov, Zemser-Werner, Valentina, Zlotnik, Oran, Kroon, Sanne, Hardt, Wolf-Dietrich, Debets, Reno, Reticker-Flynn, Nathan Edward, Rider, Peleg, Carmi, Yaron
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9489212/
https://www.ncbi.nlm.nih.gov/pubmed/36124553
http://dx.doi.org/10.7554/eLife.80315
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author Gutwillig, Amit
Santana-Magal, Nadine
Farhat-Younis, Leen
Rasoulouniriana, Diana
Madi, Asaf
Luxenburg, Chen
Cohen, Jonathan
Padmanabhan, Krishnanand
Shomron, Noam
Shapira, Guy
Gleiberman, Annette
Parikh, Roma
Levy, Carmit
Feinmesser, Meora
Hershkovitz, Dov
Zemser-Werner, Valentina
Zlotnik, Oran
Kroon, Sanne
Hardt, Wolf-Dietrich
Debets, Reno
Reticker-Flynn, Nathan Edward
Rider, Peleg
Carmi, Yaron
author_facet Gutwillig, Amit
Santana-Magal, Nadine
Farhat-Younis, Leen
Rasoulouniriana, Diana
Madi, Asaf
Luxenburg, Chen
Cohen, Jonathan
Padmanabhan, Krishnanand
Shomron, Noam
Shapira, Guy
Gleiberman, Annette
Parikh, Roma
Levy, Carmit
Feinmesser, Meora
Hershkovitz, Dov
Zemser-Werner, Valentina
Zlotnik, Oran
Kroon, Sanne
Hardt, Wolf-Dietrich
Debets, Reno
Reticker-Flynn, Nathan Edward
Rider, Peleg
Carmi, Yaron
author_sort Gutwillig, Amit
collection PubMed
description Despite the remarkable successes of cancer immunotherapies, the majority of patients will experience only partial response followed by relapse of resistant tumors. While treatment resistance has frequently been attributed to clonal selection and immunoediting, comparisons of paired primary and relapsed tumors in melanoma and breast cancers indicate that they share the majority of clones. Here, we demonstrate in both mouse models and clinical human samples that tumor cells evade immunotherapy by generating unique transient cell-in-cell structures, which are resistant to killing by T cells and chemotherapies. While the outer cells in this cell-in-cell formation are often killed by reactive T cells, the inner cells remain intact and disseminate into single tumor cells once T cells are no longer present. This formation is mediated predominantly by IFNγ-activated T cells, which subsequently induce phosphorylation of the transcription factors signal transducer and activator of transcription 3 (STAT3) and early growth response-1 (EGR-1) in tumor cells. Indeed, inhibiting these factors prior to immunotherapy significantly improves its therapeutic efficacy. Overall, this work highlights a currently insurmountable limitation of immunotherapy and reveals a previously unknown resistance mechanism which enables tumor cells to survive immune-mediated killing without altering their immunogenicity.
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spelling pubmed-94892122022-09-21 Transient cell-in-cell formation underlies tumor relapse and resistance to immunotherapy Gutwillig, Amit Santana-Magal, Nadine Farhat-Younis, Leen Rasoulouniriana, Diana Madi, Asaf Luxenburg, Chen Cohen, Jonathan Padmanabhan, Krishnanand Shomron, Noam Shapira, Guy Gleiberman, Annette Parikh, Roma Levy, Carmit Feinmesser, Meora Hershkovitz, Dov Zemser-Werner, Valentina Zlotnik, Oran Kroon, Sanne Hardt, Wolf-Dietrich Debets, Reno Reticker-Flynn, Nathan Edward Rider, Peleg Carmi, Yaron eLife Cancer Biology Despite the remarkable successes of cancer immunotherapies, the majority of patients will experience only partial response followed by relapse of resistant tumors. While treatment resistance has frequently been attributed to clonal selection and immunoediting, comparisons of paired primary and relapsed tumors in melanoma and breast cancers indicate that they share the majority of clones. Here, we demonstrate in both mouse models and clinical human samples that tumor cells evade immunotherapy by generating unique transient cell-in-cell structures, which are resistant to killing by T cells and chemotherapies. While the outer cells in this cell-in-cell formation are often killed by reactive T cells, the inner cells remain intact and disseminate into single tumor cells once T cells are no longer present. This formation is mediated predominantly by IFNγ-activated T cells, which subsequently induce phosphorylation of the transcription factors signal transducer and activator of transcription 3 (STAT3) and early growth response-1 (EGR-1) in tumor cells. Indeed, inhibiting these factors prior to immunotherapy significantly improves its therapeutic efficacy. Overall, this work highlights a currently insurmountable limitation of immunotherapy and reveals a previously unknown resistance mechanism which enables tumor cells to survive immune-mediated killing without altering their immunogenicity. eLife Sciences Publications, Ltd 2022-09-20 /pmc/articles/PMC9489212/ /pubmed/36124553 http://dx.doi.org/10.7554/eLife.80315 Text en © 2022, Gutwillig et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Gutwillig, Amit
Santana-Magal, Nadine
Farhat-Younis, Leen
Rasoulouniriana, Diana
Madi, Asaf
Luxenburg, Chen
Cohen, Jonathan
Padmanabhan, Krishnanand
Shomron, Noam
Shapira, Guy
Gleiberman, Annette
Parikh, Roma
Levy, Carmit
Feinmesser, Meora
Hershkovitz, Dov
Zemser-Werner, Valentina
Zlotnik, Oran
Kroon, Sanne
Hardt, Wolf-Dietrich
Debets, Reno
Reticker-Flynn, Nathan Edward
Rider, Peleg
Carmi, Yaron
Transient cell-in-cell formation underlies tumor relapse and resistance to immunotherapy
title Transient cell-in-cell formation underlies tumor relapse and resistance to immunotherapy
title_full Transient cell-in-cell formation underlies tumor relapse and resistance to immunotherapy
title_fullStr Transient cell-in-cell formation underlies tumor relapse and resistance to immunotherapy
title_full_unstemmed Transient cell-in-cell formation underlies tumor relapse and resistance to immunotherapy
title_short Transient cell-in-cell formation underlies tumor relapse and resistance to immunotherapy
title_sort transient cell-in-cell formation underlies tumor relapse and resistance to immunotherapy
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9489212/
https://www.ncbi.nlm.nih.gov/pubmed/36124553
http://dx.doi.org/10.7554/eLife.80315
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