SLC7A5-overexpression NK cell and SLC7A5-overexpression induced pluripotent stem cell-derived NK cells(iPSC-NK)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE344838 | GEO | 2026/09/01
REPOSITORIES: GEO
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Project description:Cell-based immunotherapy can control bulky tumors, but effector cell persistence, tumor resistance, inconsistencies of the manufactured product, and treatment cost continue to pose challenges. To address these limitations, we developed a triple gene-edited induced pluripotent stem cell (iPSC) platform for broad patient-based adoptive cell therapy. iPSCs were engineered to express a high affinity, non-cleavable version of the Fc receptor CD16a to augment antibody-mediated activity and a membrane-bound IL-15/IL-15R fusion (IL-15RF) protein to promote survival and maturation. The third edit was knockout of the ecto-enzyme CD38 that hydrolyzes NAD+ and is the target of the therapeutic antibody daratumumab. Natural killer (NK) cells derived from these iPSCs displayed metabolic features and gene expression profiles similar to those of adaptive NK cells that arise in response to cytomegalovirus (CMV) infection. These engineered iPSC-derived NK cells, termed iADAPT, persisted in vivo in the absence of exogenous cytokine and could be combined with daratumumab for efficient killing of multiple myeloma and acute myeloid leukemia cells both in vitro and in vivo. This strategy has broad off-the-shelf potential for the treatment of patients with advanced cancer.
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Project description:Metastasis remains the leading cause of mortality in lung adenocarcinoma (LUAD), yet the molecular mechanisms driving metastatic progression, particularly to the liver, remain incompletely understood. Metabolic reprogramming has emerged as a hallmark of cancer, but how amino acid transport interfaces with lipid metabolism to regulate metastasis is poorly defined. We integrated bioinformatic analysis of The Cancer Genome Atlas (TCGA) LUAD cohort with in vitro and in vivo functional studies. Weighted gene co-expression network analysis (WGCNA) was performed to identify metastasis-associated modules. SLC7A5 function was evaluated using knockdown approaches in LUAD cell lines, assessed by Western blot, wound healing, Transwell migration assays, and an orthotopic lung cancer mouse model. Mechanistic studies included RNA-seq, targeted fatty acid profiling, BODIPY FL C16 uptake assays, Seahorse FAO analysis, and PPARA luciferase reporter assays. WGCNA identified SLC7A5 as a hub gene within a metastasis-associated transcriptional network, with high expression predicting poor overall survival, disease-free survival, and liver metastasis risk in LUAD patients. SLC7A5 knockdown reversed epithelial-mesenchymal transition (EMT), suppressed cell migration in vitro, and significantly reduced intrapulmonary tumor growth in an orthotopic mouse model. Mechanistically, RNA-seq and metabolomic profiling revealed that SLC7A5 deficiency induced profound reprogramming of fatty acid metabolism, characterized by reduced exogenous fatty acid uptake, paradoxically enhanced fatty acid oxidation (FAO), and consequent intracellular fatty acid depletion. Palmitic acid supplementation rescued the migratory defects caused by SLC7A5 knockdown. Transcription factor enrichment analysis identified PPARA as a downstream effector, and SLC7A5 silencing significantly reduced PPARA expression, transcriptional activity, and the expression of its target genes governing fatty acid uptake, synthesis, and oxidation. CPT1 enzymatic activity was correspondingly diminished. Crucially, PPARA overexpression rescued the migratory defects induced by SLC7A5 knockdown, establishing PPARA as a critical functional mediator. Our study identifies SLC7A5 as a key regulator of LUAD metastasis through PPARA-mediated control of fatty acid metabolism, revealing an unexpected metabolic axis linking amino acid transport to lipid homeostasis. These findings establish SLC7A5 as a promising prognostic biomarker and therapeutic target for metastatic LUAD, particularly for patients at high risk of liver metastasis.
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Project description:Tumor antigen recognition and subsequent cytotoxic T lymphocyte (CTL) tumor infiltration are essential but alone are insufficient for an antitumor response. T cells nutrient uptake and metabolic reprogramming may dictate T cell differentiation and effector function to control CTL function in the tumor microenvironment. Slc7a5 is a system L transporter of large neutral amino acids and regulates T cell receptor (TCR)-mediated T cell activation during viral infection. Using tumor-specific CTL and antigen (Ag)-expressing tumor cell co-culture models, we determined that tumor-specific CTLs respond to tumor by increasing tryptophan uptake while responding to antigen alone without tumor cells by decreasing tryptophan uptake. ATAC-Seq analysis of the Ag-activated and tumor-activating CTLs revealed the transcriptional activation of a large set of transporters, including Slc7a5, a transporter for tryptophan. Slc7a5-specific inhibitor significantly decreased tryptophan uptake in the CTL-tumor co-culture while only tumor-specific CTLs and tumor are present in the microenvironment, indicating an essential role of Slc7a5 in transporting tryptophan in tumor-activated CTLs. We then generated mice with Slc7a5 deficiency only in T cells (Slc7a5.TKO). Transplanted breast tumor grew in a similar rate in WT and Slc7a5.TKO mice. However, Slc7a5.TKO mice formed significant more lung metastases than WTR mice. Further, transplanted melanoma tumor grew significantly faster in Slc7a5.TKO mice than in WT mice. Slc7a5.TKO mice show no significant difference in T cells as compared to WT mice. However, both CD4+ and CD8+ T cells diminished in tumors in the tumor-bearing mice, indicating an essential role of the Slc7a5-tryptophan metabolic pathway in T cell activation and expansion in the tumor microenvironment. scRNA-seq analysis determined that, unlike in the virus-infected host where MOTRC1 pathway is diminished, Slc7a5 deficiency leads to decreased AhR signaling and FasL expression in tumor-infiltrating T cells. Accordingly, FasL blockade increased lung metastases in breast tumor-bearing mice and increased tumor growth in melanoma tumor-bearing mice, indicating that Slc7a5 regulates the tryptophan-AhR metabolic pathway to regulate FasL expression in T cells to control tumor-infiltrating CTL effector function. Analysis of scRNA-seq dataset of human breast cancer patients revealed that FasL expression in T cells is correlated with SLC7A5 expression and patient response to immune checkpoint inhibitor immunotherapy. Furthermore, FasL is positively correlated with patient survival length in pooled datasets of 33 human cancers, and in human patients with breast cancer and melanoma in particular. Our findings determine that Slc7a5 controls tryptophan uptake in tumor-infiltrating CTLs to regulate the tryptophan-AhR metabolic pathway to regulate FasL expression to control CTL anti-tumor immune response.
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