Cancer stem cells release interleukin-33 within large oncosomes to promote immunosuppressive differentiation of macrophage precursors

Hannah L. Erickson, Sachiko Taniguchi, Anish Raman, Justin J. Leitenberger, Sanjay V. Malhotra, Naoki Oshimori

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

In squamous cell carcinoma (SCC), macrophages responding to interleukin (IL)-33 create a TGF-β-rich stromal niche that maintains cancer stem cells (CSCs), which evade chemotherapy-induced apoptosis in part via activation of the NRF2 antioxidant program. Here, we examined how IL-33 derived from CSCs facilitates the development of an immunosuppressive microenvironment. CSCs with high NRF2 activity redistributed nuclear IL-33 to the cytoplasm and released IL-33 as cargo of large oncosomes (LOs). Mechanistically, NRF2 increased the expression of the lipid scramblase ATG9B, which exposed an “eat me” signal on the LO surface, leading to annexin A1 (ANXA1) loading. These LOs promoted the differentiation of AXNA1 receptor+ myeloid precursors into immunosuppressive macrophages. Blocking ATG9B's scramblase activity or depleting ANXA1 decreased niche macrophages and hindered tumor progression. Thus, IL-33 is released from live CSCs via LOs to promote the differentiation of alternatively activated macrophage, with potential relevance to other settings of inflammation and tissue repair.

Original languageEnglish (US)
Pages (from-to)1908-1922.e6
JournalImmunity
Volume57
Issue number8
DOIs
StatePublished - Aug 13 2024

Keywords

  • ATG9b
  • FPR2
  • IL-33
  • annexin A1
  • cancer stem cell niche
  • cancer stem cells
  • large oncosomes
  • macrophages
  • squamous cell carcinoma
  • tumor microenvironment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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