Lactate-mediated acidification of tumor microenvironment induces apoptosis of liver-resident NK cells in colorectal liver metastasis

Cathal Harmon, Mark W. Robinson, Fiona Hand, Dalal Almuaili, Keno Mentor, Diarmaid D. Houlihan, Emir Hoti, Lydia Lynch, Justin Geoghegan, Cliona O'Farrelly

Research output: Contribution to journalArticlepeer-review

194 Scopus citations

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, were analyzed 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.

Original languageEnglish (US)
Pages (from-to)335-346
Number of pages12
JournalCancer immunology research
Volume7
Issue number2
DOIs
StatePublished - Feb 2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Medicine

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