Lipid accumulation impairs natural killer cell cytotoxicity and tumor control in the postoperative period

Abstract

Background: Natural killer (NK) cell dysfunction following cancer surgery has been shown to promote metastases. Recent studies demonstrate an emerging role for lipids in the modulation of NK cell innate responses. However, the mechanisms involved in lipid modulation of NK cell postoperative anti-tumor function are unknown. This current study will determine whether the lipid accumulation via scavenger receptors on NK cells is responsible for the increase in postoperative metastasis. Methods: Lipid content in mouse and human NK cells was evaluated by flow cytometry. NK cell scavenger receptor (SR) expression was measured by microarray analysis, validated by qRT-PCR and flow cytometry. NK cell ex vivo and in vivo tumor killing was measured by chromium-release and adoptive transfer assays, respectively. The mediating role of surgery-expanded granulocytic myeloid derived suppressor cells (gMDSC) in SR induction on NK cells was evaluated using co-culture assays. Results: NK cells in surgery-treated mice demonstrated increased lipid accumulation, which occurred via up-regulation of MSR1, CD36 and CD68. NK cells with high lipid content had diminished ability to lyse tumor targets ex vivo. Adoptive transfer of lipid-laden NK cells into NK cell-deficient mice were unable to protect against a lung tumor challenge. Granulocytic MDSC from surgery-treated mice increased SR expression on NK cells. Colorectal cancer surgical patients showed increased NK cell lipid content, higher CD36 expression, decreased granzyme B and perforin production in addition to reduced cytotoxicity in the postoperative period. Conclusions: Postoperative lipid accumulation promotes the formation of metastases by impairing NK cell function in both preclinical surgical models and human surgical colorectal cancer patient samples. Understanding and targeting the mechanisms underlying lipid accumulation in innate immune NK cells can improve prognosis in cancer surgical patients.

Upregulation of lipid metabolism genes in the breast prior to cancer diagnosis

“…The authors showed that, prior to diagnosis of breast cancer, postmenopausal women had significantly higher levels of lipolysis byproducts, free fatty acids (palmitic, arachidonic, stearic, linoleic, oleic acids), and glycerol in their plasma as In the susceptible breast stroma, we observed a downregulation of genes involved in the immune response, an increase in resting NK-related gene signature and a reduction in the IHC staining of CD45 (generic immune marker) and CD20 (B-cell marker) cells. The number and function of the local immune cells can be affected by metabolites released in the surrounding microenvironment [37][38][39] . Recent reports indicate that breast cancer cells may escape immune surveillance by releasing free fatty acids, which inhibit cytotoxic T cells 40 .…”

Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer

“…In the context of lipid homeostasis, Raichur S et al showed the opposite expression patterns, where repressed RORC activity induces expression of Cd36. In both animal and human studies, increased Cd36 expression in metabolically active tissue has been implicated in the regulation of fatty acid metabolism and lipid accumulation [35,36]. In HCC patients, the number of fatty acid responsive TFs, including HIF1α and FOS, can transcriptionally upregulate Cd36, which is closely associated with induction of epithelial-mesenchymal transition (EMT) [37].…”

Targeting Myeloid-Derived Suppressor Cells for Premetastatic Niche Disruption After Tumor Resection

“…10 Both M-MDSCs and G-MDSCs are present in distant organs and contribute to premetastatic niche formation after surgery. 11,12 A premetastatic niche is a premetastatic microenvironment in distant organs that is characterized by immunosuppression, inflammation, angiogenesis, and vascular permeability, organotropism, lymph-angiogenesis, as well as reprogramming. 13 Primary cancers induce premetastatic niches in the lungs and liver.…”

“… 10 Both M-MDSCs and G-MDSCs are present in distant organs and contribute to premetastatic niche formation after surgery. 11 , 12 …”

“…Moreover, postoperative lipid accumulation due to scavenger receptor expression by NK cells is associated with increased postoperative metastases. 12 Mouse models have revealed that surgical stress enhances the MDSC numbers while suppressing the number of tumor-associated, antigen-specific, CD8 + T cells that produce IFN-γ. 36 Therefore, both G-MDSCs and M-MDSCs are essential in the establishment of premetastatic microenvironments after primary tumor resection.…”