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

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. 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.

SUBMITTER: Bent E

PROVIDER: S-EPMC8553783 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Microenvironmental IL-6 Inhibits Anti-Cancer Immune Responses Generated by Cytotoxic Chemotherapy

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Microenvironmental IL-6 Inhibits Anti-Cancer Immune Responses Generated by Cytotoxic Chemotherapy

Project description:Microenvironmental IL-6 Inhibits Anti-Cancer Immune Responses Generated by Cytotoxic Chemotherapy

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