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Modulation of Immune Checkpoints by Chemotherapy in Human Colorectal Liver Metastases
Metastatic colorectal cancer (CRC) is a major cause of cancer-related death, and incidence is rising in younger populations (younger than 50 years). Current chemotherapies can achieve response rates above 50%, but immunotherapies have limited value for patients with microsatellite-stable (MSS) cance...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762777/ https://www.ncbi.nlm.nih.gov/pubmed/33377131 http://dx.doi.org/10.1016/j.xcrm.2020.100160 |
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author | Jabbari, Neda Kenerson, Heidi L. Lausted, Christopher Yan, Xiaowei Meng, Changting Sullivan, Kevin M. Baloni, Priyanka Bergey, Dani Pillarisetty, Venu G. Hood, Leroy E. Yeung, Raymond S. Tian, Qiang |
author_facet | Jabbari, Neda Kenerson, Heidi L. Lausted, Christopher Yan, Xiaowei Meng, Changting Sullivan, Kevin M. Baloni, Priyanka Bergey, Dani Pillarisetty, Venu G. Hood, Leroy E. Yeung, Raymond S. Tian, Qiang |
author_sort | Jabbari, Neda |
collection | PubMed |
description | Metastatic colorectal cancer (CRC) is a major cause of cancer-related death, and incidence is rising in younger populations (younger than 50 years). Current chemotherapies can achieve response rates above 50%, but immunotherapies have limited value for patients with microsatellite-stable (MSS) cancers. The present study investigates the impact of chemotherapy on the tumor immune microenvironment. We treat human liver metastases slices with 5-fluorouracil (5-FU) plus either irinotecan or oxaliplatin, then perform single-cell transcriptome analyses. Results from eight cases reveal two cellular subtypes with divergent responses to chemotherapy. Susceptible tumors are characterized by a stemness signature, an activated interferon pathway, and suppression of PD-1 ligands in response to 5-FU+irinotecan. Conversely, immune checkpoint TIM-3 ligands are maintained or upregulated by chemotherapy in CRC with an enterocyte-like signature, and combining chemotherapy with TIM-3 blockade leads to synergistic tumor killing. Our analyses highlight chemomodulation of the immune microenvironment and provide a framework for combined chemo-immunotherapies. |
format | Online Article Text |
id | pubmed-7762777 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-77627772020-12-28 Modulation of Immune Checkpoints by Chemotherapy in Human Colorectal Liver Metastases Jabbari, Neda Kenerson, Heidi L. Lausted, Christopher Yan, Xiaowei Meng, Changting Sullivan, Kevin M. Baloni, Priyanka Bergey, Dani Pillarisetty, Venu G. Hood, Leroy E. Yeung, Raymond S. Tian, Qiang Cell Rep Med Article Metastatic colorectal cancer (CRC) is a major cause of cancer-related death, and incidence is rising in younger populations (younger than 50 years). Current chemotherapies can achieve response rates above 50%, but immunotherapies have limited value for patients with microsatellite-stable (MSS) cancers. The present study investigates the impact of chemotherapy on the tumor immune microenvironment. We treat human liver metastases slices with 5-fluorouracil (5-FU) plus either irinotecan or oxaliplatin, then perform single-cell transcriptome analyses. Results from eight cases reveal two cellular subtypes with divergent responses to chemotherapy. Susceptible tumors are characterized by a stemness signature, an activated interferon pathway, and suppression of PD-1 ligands in response to 5-FU+irinotecan. Conversely, immune checkpoint TIM-3 ligands are maintained or upregulated by chemotherapy in CRC with an enterocyte-like signature, and combining chemotherapy with TIM-3 blockade leads to synergistic tumor killing. Our analyses highlight chemomodulation of the immune microenvironment and provide a framework for combined chemo-immunotherapies. Elsevier 2020-12-22 /pmc/articles/PMC7762777/ /pubmed/33377131 http://dx.doi.org/10.1016/j.xcrm.2020.100160 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Jabbari, Neda Kenerson, Heidi L. Lausted, Christopher Yan, Xiaowei Meng, Changting Sullivan, Kevin M. Baloni, Priyanka Bergey, Dani Pillarisetty, Venu G. Hood, Leroy E. Yeung, Raymond S. Tian, Qiang Modulation of Immune Checkpoints by Chemotherapy in Human Colorectal Liver Metastases |
title | Modulation of Immune Checkpoints by Chemotherapy in Human Colorectal Liver Metastases |
title_full | Modulation of Immune Checkpoints by Chemotherapy in Human Colorectal Liver Metastases |
title_fullStr | Modulation of Immune Checkpoints by Chemotherapy in Human Colorectal Liver Metastases |
title_full_unstemmed | Modulation of Immune Checkpoints by Chemotherapy in Human Colorectal Liver Metastases |
title_short | Modulation of Immune Checkpoints by Chemotherapy in Human Colorectal Liver Metastases |
title_sort | modulation of immune checkpoints by chemotherapy in human colorectal liver metastases |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762777/ https://www.ncbi.nlm.nih.gov/pubmed/33377131 http://dx.doi.org/10.1016/j.xcrm.2020.100160 |
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