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Intratumoral plasmid IL-12 expands CD8+ T cells and induces a CXCR3 signature in triple-negative breast tumors that sensitizes patient to anti-PD-1 therapy

ABSTRACT: Intratumoral plasmid IL-12 expands CD8+ T cells and induces a CXCR3 signature in triple-negative breast tumors that sensitizes patient to anti-PD-1 therapy

PROVIDER: PRJNA662914 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12623593_1.fastq.gz	Fastqsanger.gz
	SRR12623593_2.fastq.gz	Fastqsanger.gz
	SRR12623594_1.fastq.gz	Fastqsanger.gz
	SRR12623594_2.fastq.gz	Fastqsanger.gz
	SRR12623595_1.fastq.gz	Fastqsanger.gz

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Intratumoral plasmid IL-12 expands CD8+ T cells and induces a CXCR3 signature in triple-negative breast tumors that sensitizes patient to anti-PD-1 therapy

Project description:We show that plasmid IL-12 injected intratumorally followed by co-localized electroporation induces a CXCR3 gene signature with enhanced antigen presentation, expansion, and licensing of T cells systemically. We highlight a patient that was previously non-responsive to atezolizumab and nab-paclitaxel, who demonstrated significant clinical response to nivolumab following TAVOTM therapy.

2021-09-01 | GSE157819 | GEO

Intratumoral Plasmid IL12 Expands CD8<sup>+</sup> T Cells and Induces a CXCR3 Gene Signature in Triple-negative Breast Tumors that Sensitizes Patients to Anti-PD-1 Therapy.

Project description:PurposeTriple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Antibodies targeting programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) have entered the therapeutic landscape in TNBC, but only a minority of patients benefit. A way to reliably enhance immunogenicity, T-cell infiltration, and predict responsiveness is critically needed.Patients and methodsUsing mouse models of TNBC, we evaluate immune activation and tumor targeting of intratumoral IL12 plasmid followed by electroporation (tavokinogene telseplasmid; Tavo). We further present a single-arm, prospective clinical trial of Tavo monotherapy in patients with treatment refractory, advanced TNBC (OMS-I140). Finally, we expand these findings using publicly available breast cancer and melanoma datasets.ResultsSingle-cell RNA sequencing of murine tumors identified a CXCR3 gene signature (CXCR3-GS) following Tavo treatment associated with enhanced antigen presentation, T-cell infiltration and expansion, and PD-1/PD-L1 expression. Assessment of pretreatment and posttreatment tissue from patients confirms enrichment of this CXCR3-GS in tumors from patients that exhibited an enhancement of CD8+ T-cell infiltration following treatment. One patient, previously unresponsive to anti-PD-L1 therapy, but who exhibited an increased CXCR3-GS after Tavo treatment, went on to receive additional anti-PD-1 therapy as their immediate next treatment after OMS-I140, and demonstrated a significant clinical response.ConclusionsThese data show a safe, effective intratumoral therapy that can enhance antigen presentation and recruit CD8 T cells, which are required for the antitumor efficacy. We identify a Tavo treatment-related gene signature associated with improved outcomes and conversion of nonresponsive tumors, potentially even beyond TNBC.

| S-EPMC8102331 | biostudies-literature

Transcriptional analysis of murine CXCR3+ vs. CXCR3- peritoneal cavity B cells 8 days following infection with Ehrlichia muris.

Project description:We performed bulk RNA sequencing on murine CXCR3+ and CXCR3-negative live singlet IgM+ IgD-neg CD19+ CD138-neg (B1 B cell-like) peritoneal cavity B cells to compare the transcriptomes of the two populations following i.p. infection with the intracellular bacterium Ehrlichia muris. Total RNA was extracted and sequenced, followed by pseudoalignment, quality assessment, normalization, and analysis of differential gene expression. The CXCR3+ B1 B cell-like population was highly enriched for genes involved in proliferation, metabolism, and cell division, whereas the CXCR3- B1 B cell-like population transcriptionally resembled canonical B1 B cells and did not appear to be proliferative. These results suggest local proliferation of CXCR3+ B cells occurs in the peritoneal cavity during acute infection with an intracellular bacterium.

2022-04-18 | GSE190651 | GEO

T cell receptors repertoire sequencing of the human CD8+ naive subsets (CXCR3-,CXCR3+)

Project description:T cell receptors repertoire sequencing of the human CD8+ naive subsets (CXCR3-,CXCR3+)

| PRJEB31057 | ENA

Cxcl10 and Cxcr3 regulate self-renewal and differentiation of hematopoietic stem cells

Project description:Background: The function of hematopoietic stem cells (HSC) is regulated by HSC internal signaling pathways and their microenvironment. Chemokines and chemokine ligands play important roles in the regulation of HSC function. Yet, their functions in HSC are not fully understood. Methods: We established Cxcr3 and Cxcl10 knockout mouse models (Cxcr3-/- and Cxcl10-/-) to analyze the roles of Cxcr3 or Cxcl10 in regulating HSC function. The cell cycle distribution of LT-HSC was assessed via flow cytometry. Cxcr3-/-and Cxcl10-/-stem/progenitor cells showed reduced self-renewal capacity as measured in serial transplantation assays. To study the effects of Cxcr3 or Cxcl10 deficient bone marrow microenvironment, we transplanted CD45.1 donor cells into Cxcr3-/-or Cxcl10-/- recipient mice (CD45.2) and examined donor-contributed hematopoiesis. Results: Deficiency of Cxcl10 and its receptor Cxcr3 led to decreased BM cellularity in mice, with a significantly increased proportion of LT-HSC. Cxcl10-/- stem/progenitor cells showed reduced self-renewal capacity in the secondary transplantation assay. Notably, Cxcl10-/- donor-derived cells preferentially differentiated into B lymphocytes, with skewed myeloid differentiation ability. Meanwhile, Cxcr3-deficient HSCs demonstrated a reconstitution disadvantage in secondary transplantation, but the lineage bias was not significant. Interestingly, the absence of Cxcl10 or Cxcr3 in bone marrow microenvironment did not affect HSC function. Conclusions: The Cxcl10 and Cxcr3 regulate the function of HSC, including self-renewal and differentiation, adding to the understanding of the roles of chemokines in the regulation of HSC function.

2024-07-25 | GSE272747 | GEO

Amplification of the CXCR3/CXCL9 axis via intratumoral electroporation of plasmid CXCL9 synergizes with plasmid IL-12 therapy to elicit robust anti-tumor immunity.

Project description:Clinical studies have demonstrated that local expression of the cytokine IL-12 drives interferon-gamma expression and recruits T cells to the tumor microenvironment, ultimately yielding durable systemic T cell responses. Interrogation of longitudinal biomarker data from our late-stage melanoma trials identified a significant on-treatment increase of intratumoral CXCR3 transcripts that was restricted to responding patients, underscoring the clinical relevance of tumor-infiltrating CXCR3+ immune cells. In this study, we sought to understand if the addition of DNA-encodable CXCL9 could augment the anti-tumor immune responses driven by intratumoral IL-12. We show that localized IL-12 and CXCL9 treatment reshapes the tumor microenvironment to promote dendritic cell licensing and CD8+ T cell activation. Additionally, this combination treatment results in a significant abscopal anti-tumor response and provides a concomitant benefit to anti-PD-1 therapies. Collectively, these data demonstrate that a functional tumoral CXCR3/CXCL9 axis is critical for IL-12 anti-tumor efficacy. Furthermore, restoring or amplifying the CXCL9 gradient in the tumors via intratumoral electroporation of plasmid CXCL9 can not only result in efficient trafficking of cytotoxic CD8+ T cells into the tumor but can also reshape the microenvironment to promote systemic immune response.

| S-EPMC9092072 | biostudies-literature

Intratumoral heterogeneity of prostate cancers

Project description:Copy number analyses of regionally separated intratumoral biopsies of prostate cancers. Intratumoral heterogeneity (ITH) leads to regional biases of the mutational landscape in a single tumor and may influence the single biopsy-based clinical diagnosis and treatment decision. To evaluate the extent of ITH in unifocal prostate cancers (PCAs) that had not been sought, we analyzed multiple regional biopsies from three PCAs using DNA copy number analyses. DNA copy number showed ITH including regional biases in the presentation of a well-known driver of TMPRSS2-ERG fusion. Our analyses identified a substantial level of genetic ITH in unifocal PCAs at the genomic levels, which should be taken into account for the curation of biomarkers in the clinical setting. Four intratumoral biopsies were obtained per tumor for three prostate cancers. Radical prostatectomy tissue from three patients with prostate cancers were obtained. Board-certified pathologists reviewed the hematoxylin&eosin stained sections and identified tumor-rich regions (> 80% purity). We selected four different areas for biopsy that were at least 5mm apart and were comprised of the most common Gleason pattern (the most common histologic patterns with minimal histologic differences). Copy number profiling was performed using Agilent 180K platform according to the manufacturer's protocol.

2014-01-18 | E-GEOD-54185 | biostudies-arrayexpress

TXNIP loss expands Myc transcriptome

Project description:TXNIP loss expands Myc transcriptome

| PRJNA923027 | ENA

Plasmid pENVA

Project description:Plasmid pENVA

| PRJEB5291 | ENA

Pro-inflammatory Beta Cell Small Extracellular Vesicles Induce Beta Cell Failure Through Activation of the CXCL10/CXCR3 Axis in Diabetes

Project description:Coordinated communication among pancreatic islet cells is necessary for the maintenance of glucose homeostasis. In diabetes, chronic exposure to pro-inflammatory cytokines has been shown to perturb β-cell communication and function. Compelling evidence has implicated extracellular vesicles (EVs) in modulating physiological and pathological responses to β-cell stress. We report that pro-inflammatory β-cell small EVs (cytoEV) induce β-cell dysfunction, promote a pro-inflammatory islet transcriptome, and enhance recruitment of CD8+ T-cells and macrophages. Proteomic analysis of cytoEV revealed an enrichment of the chemokine, CXCL10, with surface topological analysis depicting CXCL10 as membrane-bound on cytoEV to facilitate direct binding to CXCR3 receptors on the surface of β-cells. CXCR3 receptor inhibition reduced CXCL10-cytoEV binding and attenuated β-cell dysfunction, inflammatory gene expression, and leukocyte recruitment to islets. Collectively, this work implicates the significant role of pro-inflammatory β-cell derived small EVs in modulating β-cell function, global gene expression, and antigen presentation through activation of the CXCL10/CXCR3 axis.

2021-08-25 | PXD026998 | Pride

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