IL-8 Downregulation Mediates the Beneficial Effects of Infection-Induced Fever on Breast Cancer Prognosis.

Abstract

Purpose: Previous studies have reported that infection-induced fever is associated with improved breast cancer prognosis, potentially through the modulation of cytokines. However, the key cytokines and the underlying mechanisms through which fever exerts its anti-tumor effects remain unclear.

Patients and methods: A total of 794 breast cancer patients were recruited between 2008 and 2017, with follow-up extending until October 31st, 2023. Infection-induced fever was assessed using questionnaires, while a multiplex assay evaluated a panel of 27 cytokines. The mediation effects of various cytokines were analyzed through model-based causal mediation analysis. Additionally, we explored modifications to these mediation effect by examining interactions among the cytokines themselves as well as their interactions with infection-induced fever. Bioinformatic analyses were conducted to elucidate the biological pathways mediating infection-induced fever.

Results: The relationship between infection-induced fever and improved breast cancer prognosis was mediated by a decrease in interleukin-8 (IL-8) levels. Furthermore, our findings revealed that the downregulation of IL-8, which mediates the beneficial effects of fever, was antagonized by IL-2, IL12p70 and IL-7. By intersecting the biological pathways influenced by IL-8, alongside those affected by IL-2, IL12p70, or IL-7, we found that these latter cytokines antagonized the mediation effects of IL-8 via regulating critical pathways such as neutrophil degranulation, extracellular matrix organization and asparagine N-linked glycosylation.

Conclusion: Infection-induced fever may improve breast cancer prognosis through IL-8 downregulation and the mediation mechanisms may be involved in neutrophil degranulation, extracellular matrix organization and asparagine N-linked glycosylation. Such findings not only provide valuable insights into effectively managing febrile responses for breast cancer patients, but also underscore the therapeutic potential of cytokines in breast cancer patients.