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

Eric H Bent,Daniel R Goulet,Luis R Millán-Barea,Iris Zhuang,Julia Fröse,Michael T Hemann

doi:10.1038/s41467-021-26407-4

Eric H Bent, Daniel R Goulet + Show 4 more

Open Access

https://doi.org/10.1038/s41467-021-26407-4

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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.

Highlights

Cytotoxic chemotherapeutics primarily function through DNA damage-induced tumor cell apoptosis, the inflammation provoked by these agents can stimulate anti-cancer immune responses
Overall survival was extended in tumor-bearing mice treated with doxorubicin, but all mice relapsed with chemoresistant disease (Fig. 1a)—a phenotype that parallels treatment failure in the clinical setting[31,32]
To determine the potential clinical relevance of our observations in IL-6 KO mice, we examined the efficacy of doxorubicin treatment when combined with IL-6 receptor (IL-6R) blockade in WT animals bearing B-cell acute lymphoblastic leukemia (B-ALL)

Summary

Introduction

Cytotoxic chemotherapeutics primarily function through DNA damage-induced tumor cell apoptosis, the inflammation provoked by these agents can stimulate anti-cancer immune responses. Most conventional chemotherapeutics exert their cytotoxic mechanism of action by interfering with diverse proteins that affect DNA synthesis and replication These cellular disruptions lead to the induction of genotoxic stress which results in DNA damage and in cell death[1]. Even in settings where tumor antigens are present, cytotoxic chemotherapy rarely generates durable anti-cancer immune responses This suggests that any immune stimulus from genotoxic therapy is insufficient or suppressed. Immune evasion is a hallmark of cancer development[9,10], and occurs through tumor-intrinsic changes and alterations in the diverse immune and non-immune cell types that make up the tumor microenvironment (TME)[11,12,13,14,15] Which of these are essential for repressing immune responses to cytotoxic chemotherapy is of significant interest, and has both preclinical and clinical relevance. Targeting multiple TME evasive mechanisms may potentially improve the treatment of cancer

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