Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy
Cytotoxic chemotherapeutics primarily function through DNA damage-induced tumor cell apoptosis, although the inflammation provoked by these agents can stimulate anti-cancer immune responses. The mechanisms that control these distinct effects and limit immunogenic responses to DNA-damage mediated cel...
| Main Authors: | , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2022
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| Online Access: | https://hdl.handle.net/1721.1/146807 |
| _version_ | 1811084381208444928 |
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| author | Bent, Eric H Millán-Barea, Luis R Zhuang, Iris Goulet, Daniel R Fröse, Julia Hemann, Michael T |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Bent, Eric H Millán-Barea, Luis R Zhuang, Iris Goulet, Daniel R Fröse, Julia Hemann, Michael T |
| author_sort | Bent, Eric H |
| collection | MIT |
| description | Cytotoxic chemotherapeutics primarily function through DNA damage-induced tumor cell apoptosis, although the inflammation provoked by these agents can stimulate anti-cancer immune responses. The mechanisms that control these distinct effects and limit immunogenic responses to DNA-damage mediated cell death in vivo are currently unclear. Using a mouse model of BCR-ABL+ B-cell acute lymphoblastic leukemia, we show that chemotherapy-induced anti-cancer immunity is suppressed by the tumor microenvironment through production of the cytokine IL-6. The chemotherapeutic doxorubicin is curative in IL-6-deficient mice through the induction of CD8+ T-cell-mediated anti-cancer responses, while moderately extending lifespan in wild type tumor-bearing mice. We also show that IL-6 suppresses the effectiveness of immune-checkpoint inhibition with anti-PD-L1 blockade. Our results suggest that IL-6 is a key regulator of anti-cancer immune responses induced by genotoxic stress and that its inhibition can switch cancer cell clearance from primarily apoptotic to immunogenic, promoting and maintaining durable anti-tumor immune responses. |
| first_indexed | 2024-09-23T12:49:49Z |
| format | Article |
| id | mit-1721.1/146807 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T12:49:49Z |
| publishDate | 2022 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1468072022-12-09T03:22:27Z Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy Bent, Eric H Millán-Barea, Luis R Zhuang, Iris Goulet, Daniel R Fröse, Julia Hemann, Michael T Massachusetts Institute of Technology. Department of Biology Cytotoxic chemotherapeutics primarily function through DNA damage-induced tumor cell apoptosis, although the inflammation provoked by these agents can stimulate anti-cancer immune responses. The mechanisms that control these distinct effects and limit immunogenic responses to DNA-damage mediated cell death in vivo are currently unclear. Using a mouse model of BCR-ABL+ B-cell acute lymphoblastic leukemia, we show that chemotherapy-induced anti-cancer immunity is suppressed by the tumor microenvironment through production of the cytokine IL-6. The chemotherapeutic doxorubicin is curative in IL-6-deficient mice through the induction of CD8+ T-cell-mediated anti-cancer responses, while moderately extending lifespan in wild type tumor-bearing mice. We also show that IL-6 suppresses the effectiveness of immune-checkpoint inhibition with anti-PD-L1 blockade. Our results suggest that IL-6 is a key regulator of anti-cancer immune responses induced by genotoxic stress and that its inhibition can switch cancer cell clearance from primarily apoptotic to immunogenic, promoting and maintaining durable anti-tumor immune responses. 2022-12-08T18:30:43Z 2022-12-08T18:30:43Z 2021 2022-12-08T18:27:00Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/146807 Bent, Eric H, Millán-Barea, Luis R, Zhuang, Iris, Goulet, Daniel R, Fröse, Julia et al. 2021. "Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy." Nature Communications, 12 (1). en 10.1038/S41467-021-26407-4 Nature Communications Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | Bent, Eric H Millán-Barea, Luis R Zhuang, Iris Goulet, Daniel R Fröse, Julia Hemann, Michael T Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy |
| title | Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy |
| title_full | Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy |
| title_fullStr | Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy |
| title_full_unstemmed | Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy |
| title_short | Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy |
| title_sort | microenvironmental il 6 inhibits anti cancer immune responses generated by cytotoxic chemotherapy |
| url | https://hdl.handle.net/1721.1/146807 |
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