Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-26407-4
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Funding
- Ludwig Center for Molecular Oncology at MIT
- MIT Center for Precision Cancer Medicine
- NCI [R01-CA233477, R01-CA226898, P30-CA14051]
- National Institutes of Health [T32GM007753]
- NIH/NIAID [R21AI151827]
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In a mouse model of BCR-ABL(+) B-cell acute lymphoblastic leukemia, chemotherapy-induced anti-cancer immunity is suppressed by the tumor microenvironment through production of cytokine IL-6. IL-6 inhibits the efficacy of immunotherapy and promotes resistance to doxorubicin, impacting CD8(+) T-cell-mediated anti-cancer responses.
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. Cytotoxic chemotherapy rarely generates durable anti-tumor immune responses. Here the authors show that tumor microenvironment-derived IL-6 promotes resistance to doxorubicin by suppressing CD8 T cell anti-tumor immune responses in a preclinical model of B-cell acute lymphoblastic leukemia.
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