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    Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of LiverResident NK Cells in Colorectal Liver Metastasis


    Harmon, Cathal and Robinson, Mark W. and Hand, Fiona and Almuaili, Dalal and Mentor, Keno and Houlihan, Diarmaid D. and Hoti, Emir and Lynch, Lydia and Geoghegan, Justin and O'Farrelly, Cliona (2018) Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of LiverResident NK Cells in Colorectal Liver Metastasis. Cancer Immunology Research, 7 (2). p. 2018. ISSN 2326-6066

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    Abstract

    Colorectal cancer is the third most common malignancy worldwide, with 1.3 million new cases annually. Metastasis to the liver is a leading cause of mortality in these patients. In human liver,metastatic cancer cells must evade populations of liver-resident natural killer (NK) cells with potent cytotoxic capabilities. Here, we investigated how these tumors evade liver NK-cell surveillance. Tissue biopsies were obtained from patients undergoing resection of colorectal liver metastasis (CRLM, n ¼ 18), from the tumor, adjacent tissue, and distal resection margin. The number and phenotype of liver-resident NK cells,at each site,we reanalyzed by flow cytometry. Tumor conditioned media (TCM) was generated for cytokine and metabolite quantification and used to treat healthy liver resident NK cells, isolated from donor liver perfusate during transplantation. Liver-resident NK cells were significantly depleted from CRLM tumors. Healthy liver-resident NK cells exposed to TCM underwent apoptosis in vitro,associated with elevated lactate. Tumor-infiltrating liver-resident NK cells showed signs of mitochondrial stress,which was recapitulated in vitro by treating liver-resident NK cells with lactic acid. Lactic acid induced apoptosis by decreasing the intracellular pH of NK cells,resulting in mitochondrial dysfunction that could be prevented by blocking mitochondrial ROS accumulation. CRLM tumors produced lactate, thus decreasing the pH of the tumor microenvironment. Liver-resident NK cells migrating toward the tumor were unable to regulate intracellular pH resulting in mitochondrial stress and apoptosis. Targeting CRLM metabolism provides a promising therapeutic approach to restoring local NK-cell activity and preventing tumor growth.

    Item Type: Article
    Keywords: Lactate-Mediated; Acidification; Tumor; Microenvironment; Induces Apoptosis; Liver Resident NK Cells; Colorectal Liver Metastasis;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 12652
    Identification Number: https://doi.org/10.1158/2326-6066.CIR-18-0481
    Depositing User: Mark Robinson
    Date Deposited: 27 Mar 2020 12:07
    Journal or Publication Title: Cancer Immunology Research
    Publisher: American Association for Cancer Research
    Refereed: Yes
    URI:

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