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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ABSTRACT:
PROVIDER: PRJNA1097585 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28590521_1.fastq.gz | Fastqsanger.gz | |||
| SRR28590521_2.fastq.gz | Fastqsanger.gz | |||
| SRR28590522_1.fastq.gz | Fastqsanger.gz | |||
| SRR28590522_2.fastq.gz | Fastqsanger.gz | |||
| SRR28590523_1.fastq.gz | Fastqsanger.gz |
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Project description:Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Transforming growth factor beta (TGF-β) is highly expressed in the liver tumor microenvironment and is known to inhibit immune cell activity. Here, we used human iPSCs to produce natural killer (NK) cells engineered to mediate improved anti-HCC activity. Specifically, we produced iPSC-NK cells with either knock out TGF-β receptor 2 (TGFBR2-KO) or expression of a dominant negative (DN) form of the TGF-β receptor 2 (TGFBR2-DN) combined with CARs that target either GPC3 or AFP. The TGFBR2-KO and TGFBR2-DN iPSC-NK cells are resistant to TGF-β inhibition and improved anti-HCC activity. However, expression of anti-HCC CARs on iPSC-NK cells did not lead to effective anti-HCC activity unless there was also inhibition of TGF-b activity. Our findings demonstrate that TGF-β signaling blockade is required for effective NK cell function against HCC and potentially other malignancies which express high levels of TGF-β.
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Project description:NK cells are cytotoxic lymphocytes important in defense against viral infection and cancer. NK cells mediate cytotoxicity predominantly through directed secretion of lytic granules, which are specialized lysosome-related organelles, containing effector molecules such as perforin and granzymes. Although many requirements for lytic granule transport to, and secretion at, the NK cell lytic synapse are known, the minimum number of degranulation events required by an NK cell to kill its target is unknown. We performed high-resolution four-dimensional confocal microscopy of human NK-target cell conjugates to quantify NK cell degranulation (using a degranulation indicator, LAMP-1-pHluorin) as well as target cell death. Despite containing almost 200 granules, we found that an individual NK cell needed only two to four degranulation events, on average, to mediate target cell death. Although NK cells released approximately one-tenth of their total lytic granule reserve upon a single target, they required just over one-hundredth of their total lytic granules to kill a target cell. Importantly, the kinetics of NK cell killing correlated to the size of and the amount of effector molecules contained within lytic granules, as well as the temporal, but not spatial, organization of degranulation events. Thus, our study answers a fundamental question as to how many degranulation events it takes for a human NK cell to kill its target.
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Project description:Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although bacterial lung infection and the resulting inflammation cause most of the morbidity and mortality, how loss of CFTR first disrupts airway host defense has remained uncertain. We asked what abnormality impairs elimination when a bacterium lands on the pristine surface of a newborn CF airway? To investigate this defect, we interrogated the viability of individual bacteria immobilized on solid grids and placed on the airway surface. As a model we studied CF pigs, which spontaneously develop hallmark features of CF lung disease. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria. Here we show that in newborn wild-type pigs, the thin layer of airway surface liquid (ASL) rapidly killed bacteria in vivo, when removed from the lung, and in primary epithelial cultures. Lack of CFTR reduced bacterial killing. We found that ASL pH was more acidic in CF, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defense defect to loss of CFTR, an anion channel that facilitates HCO3- transport. Without CFTR, airway epithelial HCO3- secretion is defective, ASL pH falls and inhibits antimicrobial function, and thereby impairs killing of bacteria that enter the newborn lung. These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF and that assaying ASL pH or bacterial killing could report on the benefit of therapeutic interventions. 11 samples of trachea primary airway epithelial cultures representing CFTR+/+ and CFTR-/- pigs. Pig samples representing 14 bronchus and 12 trachea tissue samples submitted in GSE21071.
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