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Osimertinib exacerbates immune checkpoint inhibitor-related severe adverse events by activating the IL-6/JAK/STAT3

Yuan Li1, Yanping Chen1,2, Yuan Meng1

  • 1Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China.

Cancer Biology & Medicine
|December 9, 2024
PubMed
Abstract

Insights

Combining EGFR-TKIs and ICIs increases severe immune-related adverse events (irAEs). Macrophage EGFR activation and IL-6/JAK/STAT3 pathway signaling drive these irAEs, offering therapeutic targets.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Immune checkpoint inhibitors (ICIs) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are crucial cancer therapies.
  • Combined use of EGFR-TKIs and ICIs increases severe immune-related adverse events (irAEs).
  • The precise mechanisms by which macrophages contribute to irAEs remain unclear.

Purpose of the Study:

  • To elucidate the role of macrophages in EGFR-TKI and ICI-induced immune-related adverse events (irAEs).
  • To investigate the underlying molecular mechanisms, specifically focusing on the IL-6/JAK/STAT3 pathway in macrophages.

Main Methods:

  • Established a mouse model of osimertinib (EGFR-TKI) and ICI-induced irAEs.
  • Utilized micro-CT, H&E staining, flow cytometry, ELISA, RNA-seq, and Western blot to analyze inflammatory responses and molecular pathways.
  • Assessed EGFR expression, cytokine levels (IL-6, TNF-α), and IL-6/JAK/STAT3 pathway activation in macrophages.

Main Results:

  • Combination therapy upregulated EGFR on macrophages and increased serum IL-6, ALT, and ferritin levels.
  • RNA-seq and Western blot confirmed activation of the IL-6/JAK/STAT3 pathway in liver macrophages.
  • Ruxolitinib, an IL-6/JAK/STAT3 inhibitor, reduced irAEs and key inflammatory markers.

Conclusions:

  • Osimertinib and ICI combination therapy activates the IL-6/JAK/STAT3 pathway in macrophages via EGFR.
  • This activation leads to cytokine release and contributes to the development of irAEs.
  • Targeting the IL-6/JAK/STAT3 pathway presents a potential strategy to mitigate irAEs.
Keywords:
ICIsIL-6/JAK/STAT3OsimertinibirAEsmacrophages

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