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Fasting reshapes tissue-specific niches to improve the innate immune response to cancer

ABSTRACT: Fasting has long been associated with the improved elimination of cancer cells. However, the distinctive role of specific immune subsets mediating these anti-tumor properties remain elusive. Using a cyclic fasting diet (CFD) after tumor initiation, we investigated the impact of fasting on NK cell anti-tumor immunity. We found that adherence to a CFD improved anti-tumor immunity against both solid and metastatic tumors in a NK cell-dependent manner. During periods of fasting, NK cells underwent tissue redistribution where NK cells in the spleen experienced tissue-specific metabolic rewiring. These NK cells were exposed to elevated concentrations of fatty acids and glucocorticoids which increased fatty acid metabolism via expression of CPT1A, and was essential for NK cell survival and anti-tumor functions. In parallel, a population of NK cells were redistributed to the bone marrow during CFD in a S1PR5- and CXCR4-dependent manner. These cells were primed by an increased pool of IL-12-expressing myeloid cells which improved IFN-g production. Together, these data uncover a novel dietary strategy to improve tumor clearance and identifies a previously unknown mechanistic link between dietary restriction and optimized innate immune responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE267467 | GEO | 2024/10/28

REPOSITORIES: GEO

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A single-cell analysis of the NK cell landscape reveals that dietary restriction boosts NK cell antitumor immunity via Eomesdermin

Project description:Natural killer (NK) cells are primarily responsible for tumor surveillance, and their activation entirely depends on optimal metabolic signals. The adaptation of NK cell anti-tumor responses to nutritional stress is still poorly understood. Here, based on single-cell RNA sequencing, we discovered that dietary restriction (DR) enriches the rejuvenated subset of CD27+CD11b+ NK cells and improves their activation via Eomesodermin (Eomes), a transcription factor upregulated during DR treatment. Eomes reverses the differentiation of rejuvenated to senescent NK cells by antagonizing the T-bet-Zeb2 axis while improving chemotaxis and adhesion. Furthermore, DR increases the chromatin accessibility of Eomes to genes that regulate chemotaxis and adhesion in NK cells. To summarize, tumor control under dietary restriction requires Eomes-regulated NK cell anti-tumor immunity.

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2024-10-17 | PXD053264 | Pride

Disruption of TGF-β signaling pathway is required to mediate effective killing of hepatocellular carcinoma by human iPSC-derived NK cells

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Bariatric surgery reduces obesity associated breast cancer and enhances response to immunotherapy [Tumor - breast cancer RNA-seq]

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Bariatric surgery reduces obesity associated breast cancer and enhances response to immunotherapy [Mammary Fat Pad RNA-seq]

2021-05-21 | GSE174760 | GEO

Proteomic analysis of NK3.3-derived extracellular vesicles

Project description:Our study investigates the features and anti-tumor function of extracellular vesicles (EVs) isolated from our well described NK cell line - NK3.3 - the only published clonal, normal human cell line to date. Natural killer (NK) cells, critical for proper immune function, destroy tumor cells primarily through the release of granules containing potent cytolytic molecules. NK cells also release these molecules within membrane-bound exosomes and microvesicles collectively known as EVs. We show that NK3.3 EVs contain the cytolytic molecules perforin, granzymes A and B, and granulysin, and an array of common EV proteins. We previously showed that the E3 ubiquitin ligase identified by our laboratory, natural killer lytic-associated molecule (NKLAM/RNF19b), is localized to NK granules and is essential for maximal NK killing; our current study shows NKLAM situated within the NK3.3 EV membrane. Analysis of NK3.3 EV contents also identified multiple RNA species including miRNAs associated with anti-tumor activity. We demonstrate that treatment of an array of hematopoietic and non-hematopoietic tumor cell lines with NK3.3 EVs inhibits proliferation and induces apoptosis and cell death while leaving normal cells unaffected. Taken together, our study suggests that NK3.3 EVs have the potential to be effective immunotherapeutic agents.

2021-09-07 | PXD027051 | Pride

Proteomic analysis of NK cell-derived extracellular vesicles.

Project description:Natural killer (NK) cells contribute to immunosurveillance and first-line defense in the control of tumor growth and metastasis diffusion. NKEVs are constitutively secreted, are biologically active, reflect the protein and genetic repertoire of their originating cells and exert anti-tumor activity in vitro and in vivo. NKEVs from tumor-conditioned NK cells interact with naïve NK cells promoting their cytotoxic activity. In cancer NK cells exhibit profound defects in degranulation ability, a status probably reflected by their NKEVs. Hence, NKEVs could contribute to improve cancer therapy by interacting with tumor and/or immune cells at the same time sensing the actual NK cell status in cancer patients. Here we investigated the role of NKEVs in stimulating the immune system and developed an immune enzymatic test (NKExoELISA) to sense the systemic NK cell status by measuring plasma NK-derived exosomes through combined capture of exosomes, expressing typical EV (tsg101) and NK cell (CD56) markers. We analyzed by LC-MS/MS the protein content from NKEVs evaluating proteins differentially expressed in exosomes (NKExo), vescicles (NKMV) and total cell extract (Tot extr) from parental NK cells. Proteomic data confirmed the presence of many EV markers and detected several proteins involved in immune response, cell adhesion and complement biological processes.

2020-04-03 | PXD014894 | Pride

Gene expression anaylsis of tumor stimulated human NK cells

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2014-03-18 | E-GEOD-55977 | biostudies-arrayexpress

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Project description:NK cells, as a type of key immune cell, play essential roles in tumor cell immune escape and immunotherapy. Accumulating evidence has demonstrated that the gut microbiota community affects the efficacy of anti-PD1 immunotherapy and that remodeling the gut microbiota structure is a promising strategy to enhance anti-PD1 immunotherapy responsiveness in advanced melanoma patients; however, the details of the mechanism remain elusive. In this study, we found that Eubacterium rectale (E. rectale) was significantly enriched in melanoma patients who responded to anti-PD1 immunotherapy and a high E. rectale abundance was related to longer survival in melanoma patients. Furthermore, administration of E. rectale remarkably improved the efficacy of anti-PD1 therapy and benefited the overall survival of tumor-bearing mice; moreover, application of E. rectale significantly recruited NK cells into the tumor microenvironment. Interestingly, conditioned medium isolated from an E. rectale culture system dramatically enhanced NK-cell function. Through GC-MS/ UHPLC-MS/MS-based metabolomic analysis, L-serine production was found to be significantly decreased in the E. rectale group; moreover, administration of an L-serine synthesis inhibitor dramatically increased NK-cell activation, which led to enhanced anti-PD1 immunotherapy effects. Mechanistically, supplementation with L-serine or application of the L-serine synthesis inhibitor affected NK-cell activation through Fos/Fosl. In summary, our findings reveal the role of bacteria-modulated serine metabolic signaling in NK-cell activation and provide a novel therapeutic strategy to improve the efficacy of anti-PD1 immunotherapy in melanoma.

2023-04-14 | GSE225920 | GEO

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Project description:N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification on RNA. NK cells are the predominant innate lymphoid cells that mediate anti-viral and anti-tumor immunity. However, whether and how m6A modifications affect NK cell immunity remains unknown. Here, we discover that YTHDF2, a well-known m6A reader, is upregulated in NK cells upon activation by cytokines, tumors, and cytomegalovirus infection. Ythdf2 deficiency in NK cells impairs NK cell anti-tumor and anti-viral activity in vivo. YTHDF2 maintains NK cell homeostasis and terminal maturation, correlating with modulating NK cell trafficking and regulating Eomes, respectively. YTHDF2 promotes NK cell effector function and is required for IL-15-mediated NK cell survival and proliferation by forming a STAT5-YTHDF2 positive feedback loop. Transcriptome-wide screening identifies Tardbp to be involved in cell proliferation or survival as a YTHDF2-binding target in NK cells. Collectively, we elucidate the biological roles of m6A modifications in NK cells and highlight a new direction to harness NK cell anti-tumor immunity.

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