Tumor-Infiltrating CTL expansion and effector functions depends on Slc7a5-dependent tryptophan update [scRNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1113354 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29079624_1.fastq.gz | Fastqsanger.gz | |||
| SRR29079624_2.fastq.gz | Fastqsanger.gz | |||
| SRR29079625_1.fastq.gz | Fastqsanger.gz | |||
| SRR29079625_2.fastq.gz | Fastqsanger.gz | |||
| SRR29079626_1.fastq.gz | Fastqsanger.gz |
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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.
2025-05-17 | GSE267839 | GEO
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.
2025-05-17 | GSE267838 | GEO
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.
2025-05-17 | GSE267840 | GEO
Project description:Tumor-Infiltrating CTL expansion and effector functions depends on Slc7a5-dependent tryptophan update
| PRJNA1113350 | ENA
Project description:Tumor-Infiltrating CTL expansion and effector functions depends on Slc7a5-dependent tryptophan update [ATAC-seq]
| PRJNA1113351 | ENA
Project description:Tumor-Infiltrating CTL expansion and effector functions depends on Slc7a5-dependent tryptophan update [RNA-seq]
| PRJNA1113352 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-05-17 | GSE267841 | GEO
Project description:The effects of loss of the large neutral amino acid transporter Slc7a5 (aka Lat1) on mouse embryonic development were investigated. Slc7a5 fl/fl mice harbouring two copies of the Slc7a5 targeted allele (exon 1 of Slc7a5 flanked with two loxP sites), were crossed with a mouse line ubiquitously expressing cre recombinase under the Bal1 promoter (Bal1-cre) to obtain a global Slc7a5 knockout mouse (Poncet et al. 2014 PLoS One 9: e89547). Heterozygous Slc7a5+/- C57Bl/6 mice were viable and fertile and were bred free of Bal1-cre in subsequent generations. Slc7a5 -/- embryos were obtained by inter-crossing heterozygotes and a phenotype was apparent by E9.5. To identify the first cellular processes affected by Slc7a5 loss RNAseq was carried out to compare transcriptomes of null and wildtype E8.5 embryos.
2019-06-01 | E-MTAB-6336 | biostudies-arrayexpress
Project description:The intestine is the critical organ not only for processing and resorbing nutrients from ingested food but also for defending the organism from external stresses such as pathogens. These functions are mainly carried out by the epithelium which is constantly being self-renewed throughout adult life. Intestinal epithelial homeostasis is maintained through well-controlled cell proliferation of the stem cells and transient amplifying cells and the apoptotic degeneration of epithelial cells, mostly at or near the tip of the villi. Many genes and pathways have been found to influence intestinal epithelial cell proliferation. Among them is the mTORC1 signaling pathway, whose activation is known to increase cell proliferation. Here, we report the first intestinal epithelial specific knockout (IEC-KO) of an amino acid transporter capable of activating mTORC1. We show that the transporter, slc7a5, is highly expressed in the intestinal crypt and slc7a5 IEC-KO leads to expected reduction in mTORC1 signal in the crypt or even in intestinal organoids in vitro. Surprisingly, slc7a5 IEC-KO leads to increased proliferation of both transit amplifying cells and crypt base stem cells but a reduction in the secretory cells, particularly mature Paneth cells in the crypt base. Our scRNA-seq and electron microscopic analyses reveals that slc7a5 IEC-KO causes dedifferentiation of the Paneth cells, leading to drastically reduced secretory granules and lysozyme expression without affecting the overall Paneth cell number. We further show that slc7a5 IEC-KO mice are prone to induced colitis due to this loss of Paneth cell differentiation. We propose a model where slc7a5 regulates secretory cell differentiation to affect stem cell niche and/or inflammatory response to regulate cell proliferation in the crypts.
2024-04-24 | GSE216930 | GEO
Project description:Gene expression analysis of WT and IL-2Ra-deficient CTL (P14) isolated 8 days after inffection with LCMV. The goals of the study are to assess the impact of IL-2 signals on effector and memory CTL differentiation.
2009-12-23 | GSE19598 | GEO