Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy

Eric H. Bent, Luis R. Millán-Barea, Iris Zhuang, Daniel R. Goulet, Julia Fröse and Michael T. Hemann ()
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Eric H. Bent: The David H. Koch Institute for Integrative Cancer Research
Luis R. Millán-Barea: The David H. Koch Institute for Integrative Cancer Research
Iris Zhuang: The David H. Koch Institute for Integrative Cancer Research
Daniel R. Goulet: The David H. Koch Institute for Integrative Cancer Research
Julia Fröse: The David H. Koch Institute for Integrative Cancer Research
Michael T. Hemann: The David H. Koch Institute for Integrative Cancer Research

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26407-4

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