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Fatty acids reshape the cytotoxicity and epigenetics of tumor-resident CD8+ T cells by maintaining SCML4 expression

ABSTRACT: To study the function of SCML4 in Trm or TILs, we established a Jurkat cell line overexpressing SCML4. We then performed gene expression profiling using data obtained by RNA-seq of Jurkat cells stably overexpressing SCML4.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214010 | GEO | 2023/08/10

REPOSITORIES: GEO

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An unconventional integrin b3 and CD103 heterodimer improves the anti-tumor immunity of tissue-resident T cells

Project description:Current cancer immunotherapies promote recovery of CD103+ tissue-resident memory T cells (Trm) population of the tumor-infiltrating T lymphocytes (TILs). However, not all treated patients exhibit improved anti-tumor immunity and survival, likely due to the immunophenotypical diversity among the CD103+ Trm TILs. Utilising multifaceted proteomics approaches and patients’ clinical analyses, we discovered an unusual subset of CD8+ Trm TILs expressing non-canonical integrin β3 early during T cells activation. The integrin β3 surprisingly heterodimerises with CD103 on T cells, leading to unconventional granulysin-mediated cytotoxicity, elevated alternative bioenergy usage and efficient T cell migration, with minimal overall exhaustion. Importantly, early-stage non-small cell lung carcinoma (NSCLC) patients with enriched presence of integrin β3+CD103+ Trm TILs exhibited better clinical prognosis, with improved T cell immunophenotype, hence confirming the beneficial role of this unusual subset of Trm TILs. These unconventional anti-tumor T cell features provide new avenues and future opportunities for designing better translational immunotherapy strategies.

2024-02-14 | PXD031794 | Pride

Fatty acids reshape the cytotoxicity and epigenetics of tumor-resident CD8+ T cells by maintaining SCML4 expression

Project description:Fatty acids reshape the cytotoxicity and epigenetics of tumor-resident CD8+ T cells by maintaining SCML4 expression

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The transcription factor Bhlhe40 programs mitochondrial regulation of resident CD8+ T cell fitness and functionality

Project description:Tissue-resident memory CD8+ T cells (Trm) share characteristics and core residency gene programs with tumor-infiltrating lymphocytes (TILs). However, the transcriptional, metabolic and epigenetic regulation of Trm cell and TIL differentiation, maintenance and function are largely undefined. Furthermore, it is unknown whether metabolic and epigenetic manipulations can be employed to promote Trm/TIL functional programs for cancer immunotherapy. Here we report a critical mechanism programming the mitochondrial and epigenetic regulation of Trm/TIL functionality in situ. We found that mouse and human Trm/TIL expressed the transcription factor BHLHE40 and the BHLHE40-associated gene signature. Bhlhe40 was specifically required for Trm and TIL development and polyfunctionality. Local PD-1 signaling inhibited TIL Bhlhe40 expression, and Bhlhe40 was critical for TILs reinvigoration following anti-PD therapy. Mechanistically, Bhlhe40 sustained Trm/TIL mitochondrial fitness for the promotion of a functional epigenetic state. Building on these findings, we also identified an epigenetic and metabolic regimen that promoted Trm/TIL gene signatures associated with tissue residency and poly-functionality through in vitro T cell screening. Strikingly, this regimen empowered the anti-tumor activity of CD8+ T cells and possessed therapeutic potential even at an advanced tumor stage in mouse models. Our results provide mechanistic insights on the local regulation of Trm and TIL function, and offer a viable strategy for developing novel immunotherapeutic means for cancer.

2019-09-17 | GSE135278 | GEO

Molecular signature of brain resident memory CD8+ T cells

Project description:Tissue resident memory (Trm) represent a newly described memory T cell population. We have previously characterized a population of Trm that persists within the brain following acute virus infection. Although capable of providing marked protection against a subsequent local challenge, brain Trm do not undergo recall expansion following dissociation from the tissue. Furthermore, these Trm do not depend on the same survival factors as the circulating memory T cell pool as assessed either in vivo or in vitro. To gain greater insight into this population of cells we compared the gene-expression profiles of Trm isolated from the brain to circulating memory T cells isolated from the spleen following an acute virus infection. Trm displayed altered expression of genes involved in chemotaxis, expressed a distinct set of transcription factors and overexpressed several inhibitory receptors. Cumulatively, these data indicates that Trm are a distinct memory T cell population disconnected from the circulating memory T cell pool and displaying a unique molecular signature which likely results in optimal survival and function within their local environment. 13 samples were analyzed: 5 replicates of memory OT-I CD8+.CD103- T cells isolated from the spleen of mice on day 20 p.i. with VSV-OVA. 5 replicates of memory OT-I CD8+CD103+ T cells isolated from the brain of mice on day 20 p.i. with VSV-OVA; and 3 replicates of memory OT-I.CD8+ CD103- T cells isolated from the brain of mice on day 20 p.i. with VSV-OVA

2012-08-29 | E-GEOD-39152 | biostudies-arrayexpress

CD49a expression and induction of cytotoxicity on human tissue-resident CD8+ T cells is controlled by RUNX2 and RUNX3 transcription factor activity [ATAC-seq]

Project description:CD49a marks highly cytotoxic epidermal tissue-resident memory (TRM)-cells, but their molecular circuitry and relationships to circulating populations are poorly defined. We demonstrate enrichment of RUNX family transcription factor binding motifs in human epidermal CD8+CD103+CD49a+ TRM-cells, paralleled by high RUNX2 and RUNX3 protein expression. Clonal overlap between epidermal CD8+CD103+CD49a+ TRM-cells and circulating memory CD8+CD45RA–CD62L+ T-cells identified a reservoir of circulating cells with potential to seed cytotoxic TRM-cells in new sites. Upon IL-15 and TGF-β stimulation, subsets of circulating CD8+CD45RA–CD62L+ T-cells acquired CD49a expression and cytotoxic transcriptional profiles in a RUNX2 and RUNX3 dependent manner. In contrast, knock-out of RUNX3, but not RUNX2, prevented CD103 expression. In melanoma, high RUNX2, but not RUNX3, transcription correlated with a cytotoxic CD8+CD103+CD49a+ TRM cell signature and overall patient survival. Together, our results indicate that combined RUNX2 and RUNX3 activity promotes the differentiation of cytotoxic CD8+CD103+CD49a+ TRM-cells, providing immunosurveillance of infected and malignant cells.

2024-04-30 | GSE232238 | GEO

CD49a expression and induction of cytotoxicity on human tissue-resident CD8+ T cells is controlled by RUNX2 and RUNX3 transcription factor activity [RNA-seq]

2024-04-30 | GSE232236 | GEO

Bulk RNA sequencing of TRM and ReCirculating CD8+ T cells from 7 HGSOC tumors

Project description:Purpose: Characterization of the gene expression profile of CD8+ TILs (TRM vs. re-circulating) from 7 HGSOC

2022-03-07 | GSE194383 | GEO

Single cell sequencing of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis

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| EGAS00001002845 | EGA

single-cell RNA and TCR sequencing of TRM CD8+ T cells sorted from 8 HGSOC tumors

Project description:Purpose: Characterization of the gene expression profile and TCR profile of CD8+ TILs (TRM and re-circulating) from HGSOC to understand the immunogenicity of ovarian cancer

2022-03-07 | GSE194105 | GEO

single-cell RNA and TCR sequencing of TRM and ReCirulating CD8+ T cells sorted from 4 HGSOC tumors

Project description:Purpose: Characterization of the gene expression profile and TCR profile of CD8+ TILs (TRM and re-circulating) from HGSOC to understand the immunogenicity of ovarian cancer

2022-03-07 | GSE193371 | GEO

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