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The mRNA and lncRNA profiles of the T cells activated by breast tumor-specific DCs pulsed by MDA-MB-231 lysates at day 0, day 1 and day 6

ABSTRACT: Activation induced cell death (AICD) of T lymphocytes may be exploited by cancers to eliminate cytotoxic T cells (CTLs). Here, we demonstrated excessive apoptosis of tumor antigen-specific CTLs in breast and lung cancers. Interestingly, NKILA, an NF-κB interacting lncRNA, sensitizes CTLs to AICD by inhibiting NF-κB activities after their activation. In vivo, administering CTLs with NKILA silencing into immunocompromised mice with breast cancer patient derived xenografts (PDXs) effectively inhibits PDX growth by increasing CTL infiltration. Clinically, NKILA was overexpressed in the tumor specific CTLs of breast and lung cancers, which was associated with less CTL infiltration in the tumors and shorter patient survival. Our findings present the first evidence that AICD in patient tumor-specific CTLs is crucial to cancer immune evasion, and targeting NKILA in CTLs emerges as a novel anti-tumor immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE108819 | GEO | 2018/07/23

REPOSITORIES: GEO

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Tumor-associated macrophages expressing the transcription factor IRF8 promote T cell exhaustion in cancer

Project description:Tumor progression is associated with overstimulation of cytotoxic T lymphocytes (CTLs), resulting in a dysfunctional state of exhaustion. However, the identity of antigen-presenting cells that drive CTL exhaustion is poorly defined. Here we show that tumor-associated macrophages (TAMs) expressing the transcription factor interferon regulatory factor-8 (IRF8) promote CTL exhaustion in a murine model of breast cancer. While CTL priming in tumor-draining lymph nodes was enabled by IRF8-dependent type 1 dendritic cells, CTL exhaustion in tumor required TAM expression of IRF8 that supported the cancer cell antigen-presenting function of TAMs. Macrophage-specific ablation of IRF8 reversed exhaustion of cancer cell antigen-reactive CTLs, and suppressed tumor growth. Analysis of the immune-infiltrated human renal cell carcinoma tumors revealed abundant TAMs that expressed IRF8 and were enriched for an IRF8 gene expression signature. Furthermore, the TAM-IRF8 signature co-segregated with CTL exhaustion signatures across multiple cancer types. Thus, CTL exhaustion is promoted by TAMs via IRF8.

2022-09-06 | GSE212643 | GEO

VESTIGIAL-LIKE 1 IS A SHARED TARGETABLE CANCER-PLACENTA ANTIGEN EXPRESSED BY PANCREATIC AND BASAL-LIKE BREAST CANCERS

Project description:Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regression by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from tumor specimens of 35 PDAC patients. This led to the identification of a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1), a novel putative TAA demonstrating overexpression in multiple tumor types and low or absent transcript expression in essential normal tissues. VGLL1-specific CTLs isolated and expanded from the blood of a male PDAC patient showed the capacity to recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung and basal-like breast cancers. Gene expression profiling revealed that VGLL1 is a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic TAA targets for patients with multiple different cancer types.

2020-10-19 | PXD018302 | Pride

IFN-γ Upregulates Survivin and Ifi202 Expression to Induce Survival and Proliferation of Tumor-Specific T Cells

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2010-12-03 | E-GEOD-22890 | biostudies-arrayexpress

ShcA is a Paracrine Integrator of the Adaptive Immune Response during Breast Cancer Progression

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2010-10-12 | E-GEOD-18996 | biostudies-arrayexpress

ShcA is a Paracrine Integrator of the Adaptive Immune Response during Breast Cancer Progression

2010-10-12 | GSE18996 | GEO

IFN-γ Upregulates Survivin and Ifi202 Expression to Induce Survival and Proliferation of Tumor-Specific T Cells

2010-12-03 | GSE22890 | GEO

DICER controls macrophage polarization and tumor response to immunotherapy

Project description:Tumor-associated macrophages (TAMs) have immunosuppressive capacity in mouse models of cancer. Here we show that the genetic deletion of the microRNA (miRNA)-processing enzyme DICER in TAMs broadly programs them to a CD11c+MRC1−/low M1-like immunostimulatory phenotype characterized by activated interferon-γ (IFN-γ)/STAT1/IRF signaling. M1-like TAM programming fostered the recruitment of cytotoxic T-cells (CTLs), including tumor-antigen-specific CTLs, inhibited tumor growth, and enhanced the efficacy of PD1 checkpoint blockade. Bioinformatics analysis of TAM transcriptomes identified a limited set of miRNAs putatively involved in TAM programming. Re-expression of Let-7 in Dicer-deficient TAMs was sufficient to partly rescue the M2-like (protumoral) TAM phenotype and abate tumor CTL infiltration. Targeted suppression of DICER activity in TAMs may, therefore, stimulate antitumor immunity and enhance the efficacy of cancer immunotherapy.

2016-06-13 | GSE76356 | GEO

A Study of Type-1 Polarized Dendritic Cell (αDC1) Vaccine in Combination With Tumor-Selective Chemokine Modulation (Interferon-α2b, Rintatolimod, and Celecoxib) in Subjects With Chemo-Refractory Metastatic Colorectal Cancer

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Expression data from P14 TCR cytotoxic T cells overexpressing HDAC7 phosphorylation deficient mutant

Project description:The present study reports an unbiased analysis of the cytotoxic T cell serine-threonine phosphoproteome using high resolution mass spectrometry. Approximately 2,000 phosphorylations were identified in CTLs of which approximately 450 were controlled by TCR signaling. A significantly overrepresented group of molecules identified in the phosphoproteomic screen were transcription activators, co-repressors and chromatin regulators. A focus on the chromatin regulators revealed that CTLs have high expression of the histone deacetylase HDAC7 but continually phosphorylate and export this transcriptional repressor from the nucleus. HDAC7 dephosphorylation results in its nuclear accumulation and suppressed expression of genes encoding key cytokines, cytokine receptors and adhesion molecules that determine CTL function. The screening of the CTL phosphoproteome thus reveals intrinsic pathways of serine-threonine phosphorylation that target chromatin regulators in CTLs and determine the CTL functional program. We used Affymetrix microarray analysis to explore the molecular basis for the role of HDAC7 in CTLs and the impact of GFP-HDAC7 phosphorylation deficient mutant expression on the CTL transcriptional profile. In vitro generated P14 TCR cytotoxic T cells were retrovirally infected with a construct encoding GFP-HDAC7 phosphorylation deficient mutant, sorted in base of GFP expression (GFP positive and GFP negative) and processed for microarray analysis in three biological replicas.

2011-03-13 | E-GEOD-27092 | biostudies-arrayexpress

A microRNA-directed program of cytotoxic CD8+ T cell differentiation

Project description:Acquisition of effector properties is a key step in the generation of cytotoxic T lymphocytes (CTLs). Here we show that inflammatory signals regulate Dicer expression in CTL, and that deletion or depletion of Dicer in mouse or human activated CD8+ T cells causes upregulation of perforin, granzyme and effector cytokines. Genome-wide analysis of miRNA changes induced by exposure of differentiating CTLs to IL-2 and inflammatory signals identifies miR-139 and miR-150 as components of a miRNA network that controls perforin, eomesodermin (Eomes) and IL-2Ra expression in differentiating CTLs and whose activity is modulated by IL-2, inflammation and antigenic stimulation. Overall our data show that strong IL-2R and inflammatory signals act through Dicer and miRNAs to control the cytolytic program and other aspects of effector CTL differentiation. Comparison of control and Dicer knock-out CTLs differentiated in vitro; Comparison of wild type CTLs differentiated in vitro with or without inflammatory stimuli; Comparison of effector and memory precursor CTLs isolated from mice infected with LCMV-Armstrong

2013-12-02 | E-GEOD-51393 | biostudies-arrayexpress

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