Tumor stage-driven disruption of NK cell maturation and cytotoxic functions in the lung tumor microenvironment
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ABSTRACT:
PROVIDER: PRJNA1169058 | ENA |
REPOSITORIES: ENA
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Project description:Natural Killer (NK) cells play a pivotal role against cancer, both by direct killing of malignant cells and by promoting adaptive immune response though cytokine and chemokine secretion. In the lung tumor microenvironment (TME), NK cells are scarce and dysfunctional, but the underlying mechanisms are still unclear. By conducting single-cell transcriptomic analysis of lung tumors, and exploring pseudotime, we uncovered that the TME disrupts the maturation trajectory of NK cells in a tumor stage-dependent manner, ultimately resulting in the selective exclusion of the cytotoxic subset. Using functional assays, we observed intratumoral NK cell death and a reduction in cytotoxic capacities depending the tumor stage. Finally, our analyses of human public dataset on lung cancer corroborate these findings, revealing a parallel dysfunctional maturation process of NK cells during tumor progression. These results highlight novel mechanisms by which tumor cells escape from NK cell cytotoxicity, therefore paving the way for tailored therapeutic strategies.
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Project description:Genome wide expression profiling of human NK cells stimulated with K562 erythroleukemic tumor cells after four hours of NK-tumor co-culture. Responding NK cells were compared to non-responding NK cells, delineated by display of CD107 on the NK cell surface following cytotoxic granule release. We hypothesized that tumor responses would initiate rapid changes in gene expression in the NK cell that would identify new features of the anti-tumor response of NK cells. Results identify NK cell activation responses and induction of TNF superfamily molecules with immunoregulatory activity.
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Project description:Resistance of tumor cells to cell-mediated cytotoxicity remains a drawback in the immunotherapy of cancer and its molecular basis is poorly understood. To investigate the acquisition of tumor resistance to cell-mediated cytotoxicity, resistant variants were selected following long term NK cell selection pressure. We found that these variants are resistant to NK cell-mediated lysis but still sensitive to autologous cytotoxic T lymphocytes or cytotoxic drugs. This resistance seems to be dependent, at least partly, of an alteration of the target cell recognition by NK effector cells, but does not appear to involve any alteration of KIR, DNAM1 or NKG2D ligands expression on resistant cells nor the induction of a protective autophagy. To gain further insight into the molecular mechanisms underlying the acquired tumor resistance to NK cells-mediated cytotoxicity, we have conducted a comprehensive analysis of the variants transcriptome. Comparative analysis identified an expression profile of genes that best distinguished resistant variant from parental sensitive cancer cells with candidate genes putatively involved in NK cell-mediated lysis resistance, but also in adhesion, migration and invasiveness including up-regulated genes such as POT1, L1CAM or ECM1 and down-regulated genes like B7-H6 or UCHL1. Consequently, the selected variants did not only display resistance to NK cell-mediated lysis but also exhibited more aggressive properties. The present studies emphasize that NK cells expand far beyond the simple killing of malignant cells and may be important effectors during cancer immunoediting.This study aims to compare transcriptome of T1_ref cells (2 triplicates samples untreated versus 2 triplicate samples of T1 after cocultured with NK cells).
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Project description:Natural killer (NK) cells are critical to immune surveillance against infections and cancer. Their role in immune surveillance requires that NK cells are present within tissues in a quiescent state. Mechanisms by which NK cells remain quiescent in tissues are incompletely elucidated. The transcriptional repressor BACH2 plays a critical role within the adaptive immune system, but its function within innate lymphocytes has been unclear. Here, we show that BACH2 acts as an intrinsic negative regulator of NK cell maturation and function. BACH2 is expressed within developing and mature NK cells and promotes the maintenance of immature NK cells by restricting their maturation in the presence of weak stimulatory signals. Loss of BACH2 within NK cells results in accumulation of activated NK cells with unrestrained cytotoxic function within tissues, which mediate augmented immune surveillance to pulmonary cancer metastasis. These findings establish a critical function of BACH2 as a global negative regulator of innate cytotoxic function and tumor immune surveillance by NK cells.
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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.
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Project description:Antibodies targeting “immune checkpoints” have revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes, primarily CD8 T cells. Interest in targeting analogous pathways in other cytotoxic lymphocytes is growing. Natural killer (NK) cells are key to cancer immunosurveillance by eradicating metastases and driving solid tumor inflammation. NK cell anti-tumor function is dependent on the cytokine interleukin (IL)-15. Ablation of the IL-15 signaling inhibitor CIS (Cish) enhances NK cell anti-tumor immunity by increasing NK cell metabolism and persistence within the tumor microenvironment (TME). The TME has also been shown to impair NK cell fitness via the production of immunosuppressive TGF-b, a suppression which occurs even in the presence of high IL-15 signaling. Here, we identified an unexpected interaction between CIS and the TGF-b signaling pathway in NK cells. Independently, Cish- and Tgfbr2- deficient NK cells are both hyper-responsive to IL-15 and hypo-responsive to TGF-b, with dramatically enhanced anti-tumor immunity. Remarkably, when both these immunosuppressive genes are simultaneously deleted in NK cells, mice are largely resistant to tumor development, suggesting that combining suppression of these two pathways might represent a novel therapeutic strategy to enhance innate anti-cancer immunity.
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