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Macrophage-secreted interleukin-35 regulates cancer cell plasticity to facilitate metastatic colonization

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  • Chih-Chan Lee

    (National Yang-Ming University and Academia Sinica)

  • Jiunn-Chang Lin

    (MacKay Memorial Hospital and MacKay Medical College
    MacKay Junior College of Medicine, Nursing, and Management)

  • Wei-Lun Hwang

    (National Yang-Ming University)

  • Ying-Ju Kuo

    (Taipei Veterans General Hospital)

  • Hung-Kai Chen

    (Elixiron Immunotherapeutics Inc.)

  • Shyh-Kuan Tai

    (Taipei Veterans General Hospital)

  • Chun-Chi Lin

    (Taipei Veterans General Hospital)

  • Muh-Hwa Yang

    (National Yang-Ming University and Academia Sinica
    National Yang-Ming University
    National Yang-Ming University
    Taipei Veterans General Hospital)

Abstract

A favorable interplay between cancer cells and the tumor microenvironment (TME) facilitates the outgrowth of metastatic tumors. Because of the distinct initiating processes between primary and metastatic tumors, we investigate the differences in tumor-associated macrophages (TAMs) from primary and metastatic cancers. Here we show that dual expression of M1 and M2 markers is noted in TAMs from primary tumors, whereas predominant expression of M2 markers is shown in metastatic TAMs. At metastatic sites, TAMs secrete interleukin-35 (IL-35) to facilitate metastatic colonization through activation of JAK2–STAT6-GATA3 signaling to reverse epithelial–mesenchymal transition (EMT) in cancer cells. In primary tumors, inflammation-induced EMT upregulates IL12Rβ2, a subunit of the IL-35 receptor, in cancer cells to help them respond to IL-35 during metastasis. Neutralization of IL-35 or knockout of IL-35 in macrophages reduces metastatic colonization. These results indicate the distinct TMEs of primary and metastatic tumors and provide potential targets for intercepting metastasis.

Suggested Citation

  • Chih-Chan Lee & Jiunn-Chang Lin & Wei-Lun Hwang & Ying-Ju Kuo & Hung-Kai Chen & Shyh-Kuan Tai & Chun-Chi Lin & Muh-Hwa Yang, 2018. "Macrophage-secreted interleukin-35 regulates cancer cell plasticity to facilitate metastatic colonization," Nature Communications, Nature, vol. 9(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06268-0
    DOI: 10.1038/s41467-018-06268-0
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    Cited by:

    1. Dinh-Huy Nguyen & Sung-Hwan You & Hien Thi-Thu Ngo & Khuynh Nguyen & Khang Vuong Tran & Tan-Huy Chu & So-young Kim & Sang-Jun Ha & Yeongjin Hong & Jung-Joon Min, 2024. "Reprogramming the tumor immune microenvironment using engineered dual-drug loaded Salmonella," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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