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IKKa-deficient lung adenocarcinomas generate an immunosuppressive microenvironment by overproducing Treg-inducing cytokines

  1. Author:
    Song, Na-Young
    Li,Xin
    Ma, Buyong [ORCID]
    Willette-Brown, Jami
    Zhu,Feng
    Jiang, Chengfei
    Su,Ling
    Shetty,Jyoti
    Zhao,Yongmei
    Shi,Gongping [ORCID]
    Banerjee, Sayantan
    Wu,Xiaolin
    Tran,Bao
    Nussinov,Ruth
    Karin, Michael [ORCID]
    Hu,Yinling [ORCID]

  2. Author Address

    Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, NIH, Frederick, MD 21702., Laboratory of Cancer Immunometabolism, Frederick National Laboratory for Cancer Research, Frederick, MD 21702., Cardiovascular Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892., Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701., Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093 karinoffice@health.ucsd.edu huy2@mail.nih.gov., Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, NIH, Frederick, MD 21702; karinoffice@health.ucsd.edu huy2@mail.nih.gov.,
    1. Year: 2022
    2. Date: Feb 08
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 119
    2. 6
    3. Pages: e2120956119
  4. Type of Article: Article
  1. Abstract:

    The tumor microenvironment (TME) provides potential targets for cancer therapy. However, how signals originating in cancer cells affect tumor-directed immunity is largely unknown. Deletions in the CHUK locus, coding for I?B kinase a (IKKa), correlate with reduced lung adenocarcinoma (ADC) patient survival and promote KrasG12D-initiated ADC development in mice, but it is unknown how reduced IKKa expression affects the TME. Here, we report that low IKKa expression in human and mouse lung ADC cells correlates with increased monocyte-derived macrophage and regulatory T cell (Treg) scores and elevated transcription of genes coding for macrophage-recruiting and Treg-inducing cytokines (CSF1, CCL22, TNF, and IL-23A). By stimulating recruitment of monocyte-derived macrophages from the bone marrow and enforcing a TNF/TNFR2/c-Rel signaling cascade that stimulates Treg generation, these cytokines promote lung ADC progression. Depletion of TNFR2, c-Rel, or TNF in CD4+ T cells or monocyte-derived macrophages dampens Treg generation and lung tumorigenesis. Treg depletion also attenuates carcinogenesis. In conclusion, reduced cancer cell IKKa activity enhances formation of a protumorigenic TME through a pathway whose constituents may serve as therapeutic targets for KRAS-initiated lung ADC. Copyright © 2022 the Author(s). Published by PNAS.

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External Sources

  1. View Full Text
  2. DOI: 10.1073/pnas.2120956119
  3. PMID: 35121655
  4. PII : 2120956119

Library Notes

  1. Fiscal Year: FY2021-2022
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