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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-09-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/80315 |
| _version_ | 1811203183724199936 |
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| author | Amit Gutwillig Nadine Santana-Magal Leen Farhat-Younis Diana Rasoulouniriana Asaf Madi Chen Luxenburg Jonathan Cohen Krishnanand Padmanabhan Noam Shomron Guy Shapira Annette Gleiberman Roma Parikh Carmit Levy Meora Feinmesser Dov Hershkovitz Valentina Zemser-Werner Oran Zlotnik Sanne Kroon Wolf-Dietrich Hardt Reno Debets Nathan Edward Reticker-Flynn Peleg Rider Yaron Carmi |
| author_facet | Amit Gutwillig Nadine Santana-Magal Leen Farhat-Younis Diana Rasoulouniriana Asaf Madi Chen Luxenburg Jonathan Cohen Krishnanand Padmanabhan Noam Shomron Guy Shapira Annette Gleiberman Roma Parikh Carmit Levy Meora Feinmesser Dov Hershkovitz Valentina Zemser-Werner Oran Zlotnik Sanne Kroon Wolf-Dietrich Hardt Reno Debets Nathan Edward Reticker-Flynn Peleg Rider Yaron Carmi |
| author_sort | Amit Gutwillig |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T02:51:21Z |
| format | Article |
| id | doaj.art-fb33e4cafa1a4209ba1b058808d753b4 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:51:21Z |
| publishDate | 2022-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-fb33e4cafa1a4209ba1b058808d753b42022-12-22T03:50:59ZengeLife Sciences Publications LtdeLife2050-084X2022-09-011110.7554/eLife.80315Transient cell-in-cell formation underlies tumor relapse and resistance to immunotherapyAmit Gutwillig0Nadine Santana-Magal1Leen Farhat-Younis2Diana Rasoulouniriana3Asaf Madi4https://orcid.org/0000-0003-3441-3228Chen Luxenburg5Jonathan Cohen6Krishnanand Padmanabhan7Noam Shomron8Guy Shapira9https://orcid.org/0000-0001-9376-4955Annette Gleiberman10https://orcid.org/0000-0002-4155-4224Roma Parikh11Carmit Levy12Meora Feinmesser13Dov Hershkovitz14Valentina Zemser-Werner15Oran Zlotnik16Sanne Kroon17https://orcid.org/0000-0002-5722-0763Wolf-Dietrich Hardt18https://orcid.org/0000-0002-9892-6420Reno Debets19https://orcid.org/0000-0002-3649-807XNathan Edward Reticker-Flynn20Peleg Rider21Yaron Carmi22https://orcid.org/0000-0002-0972-0616Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelDepartment of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelDepartment of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelDepartment of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelDepartment of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelCell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelCell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelCell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelCell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelCell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelDepartment of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelHuman Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelHuman Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelDepartment of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Institute of Pathology, Rabin Medical Center- Beilinson Hospital, Petach Tikva, IsraelDepartment of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, IsraelInstitute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, IsraelDepartment of General Surgery, Rabin Medical Center- Beilinson Campus, Petach Tikva, IsraelDepartment of Biology, Institute of Microbiology, Zurich, SwitzerlandDepartment of Biology, Institute of Microbiology, Zurich, SwitzerlandDepartment of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, NetherlandsSchool of Medicine, Department of Pathology, Stanford University, Stanford, United StatesDepartment of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelDepartment of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelDespite 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.https://elifesciences.org/articles/80315immunotherapycancer immunologycell in cellentosis |
| spellingShingle | Amit Gutwillig Nadine Santana-Magal Leen Farhat-Younis Diana Rasoulouniriana Asaf Madi Chen Luxenburg Jonathan Cohen Krishnanand Padmanabhan Noam Shomron Guy Shapira Annette Gleiberman Roma Parikh Carmit Levy Meora Feinmesser Dov Hershkovitz Valentina Zemser-Werner Oran Zlotnik Sanne Kroon Wolf-Dietrich Hardt Reno Debets Nathan Edward Reticker-Flynn Peleg Rider Yaron Carmi Transient cell-in-cell formation underlies tumor relapse and resistance to immunotherapy eLife immunotherapy cancer immunology cell in cell entosis |
| 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 | immunotherapy cancer immunology cell in cell entosis |
| url | https://elifesciences.org/articles/80315 |
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