Complete tumor regression by hetIL-15 locoregional administration is associated with a novel intratumoral CD103intCD11b+ dendritic cell population
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ABSTRACT:
PROVIDER: PRJNA749247 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15224013.fastq.gz | Fastqsanger.gz | |||
| SRR15224014.fastq.gz | Fastqsanger.gz | |||
| SRR15224015.fastq.gz | Fastqsanger.gz | |||
| SRR15224016.fastq.gz | Fastqsanger.gz | |||
| SRR15224017.fastq.gz | Fastqsanger.gz |
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Project description:Locoregional administration of heterodimeric IL-15 (hetIL-15) in a triple-negative breast cancer (TNBC) mouse model resulted in tumor eradication in 40% of treated mice, reduction of metastasis and induction of immunological memory against breast cancer cells. hetIL-15 re-shaped the tumor microenvironment by promoting the intratumoral accumulation of cytotoxic lymphocytes, conventional type 1 dendritic cells (cDC1) and a distinct DC population expressing both CD11b and CD103. These CD103intCD11b+DC share phenotypic and gene expression characteristics of both cDC1 and cDC2, have transcriptomic profile similar to monocyte-derived DC (moDC) and they correlate with tumor regression. Therefore, hetIL-15, a factor directly affecting lymphocytes and inducing cytotoxic cells, has also rapid and significant effects on the recruitment of myeloid cells, initiating a cascade for tumor elimination though innate and adoptive immune mechanisms. Our findings suggest a role for hetIL-15 in the treatment of breast cancer.
2021-07-30 | GSE180695 | GEO
Project description:hetIL-15 locoregional administration
| PRJNA942301 | ENA
Project description:Locoregional monotherapy with heterodimeric IL-15 (hetIL-15) in a triple-negative breast cancer (TNBC) orthotopic mouse model resulted in tumor eradication in 40% of treated mice, reduction of metastasis and induction of immunological memory against breast cancer cells. hetIL-15 re-shaped the tumor microenvironment by promoting the intratumoral accumulation of cytotoxic lymphocytes, conventional type 1 dendritic cells (cDC1s) and a novel DC population expressing both CD103 and CD11b markers. These CD103intCD11b+DCs share phenotypic and gene expression characteristics with both cDC1s and cDC2s, have transcriptomic profiles more similar to monocyte derived DCs (moDCs) and correlate with tumor regression. Therefore, hetIL-15, a cytokine directly affecting lymphocytes and inducing cytotoxic cells, has also an indirect rapid and significant effect on the recruitment of myeloid cells, initiating a cascade for tumor elimination though innate and adoptive immune mechanisms. The intratumoral CD103intCD11b+DC population induced by hetIL-15 may be targeted for the development of additional cancer immunotherapy approaches.
2023-03-27 | GSE226932 | GEO
Project description:Tumor eradication by hetIL-15 locoregional administration is related to intratumoral accumulation of a novel CD103intCD11b+dendritic cell population
| PRJNA942281 | ENA
Project description:Poly I:C is a powerful immune adjuvant as a result of its agonist activities on TLR-3, MDA5 and RIG-I. Intratumoral administration is conceivably safer than systemic delivery and allows concentrate proinflammatory adjuvanticity in the tumor microenvironment and tumor-draining lymphoid tissue. BO-112 is a nanoplexed formulation of Poly I:C complexed with polyethylenimine that causes tumor cell apoptosis showing immunogenic cell death features and that upon intratumoral release results in more prominent tumor infiltration by T lymphocytes. Intratumoral treatment of subcutaneous tumors derived from MC38, 4T1 and B16F10 with BO-112 leads to remarkable local disease control mediated by CD8+ T lymphocytes, as concluded from selective depletion experiments. Some degree of control of non-injected tumor lesions upon BO-112 intratumoral treatment was found in mice bearing bilateral B16OVA melanomas, that was enhanced when co-treated with systemic anti-CD137 and anti-PD-L1 immunomodulatory mAbs. More abundant CD8+ T lymphocytes were found in tumor-draining lymph nodes and in the tumor microenvironment following intratumoral treatment with BO-112. Enhanced numbers of tumor-specific CTLs recognizing melanosomal antigens and ovalbumin were readily detected among them. Genome-wide transcriptome analyses of injected tumor lesions were consistent with a marked upregulation of the type-I interferon pathway. Intratumorally delivered BO-112 is being tested in cancer patients (NCT02828098) and our results in mice suggest prominent anti-tumor local control through its proimmune effects. Intratumoral administration of BO-112, a nanoplexed form of PolyI:C, triggers an efficacious antitumor response in different tumor models as a consequence of proimmflamatory activity and its direct effects in tumor cells. BO-112 local administration induces direct tumor cell death by apoptosis, showing signs of immunogenic cell death, and a strong release of IFNα/β and other proinflammatory mediators. As a result, a tumor-specific CD8+ immune response is mounted or augmented to the point of controlling tumor progression both in the locally injected lesion and to some extent on distantly implanted tumor nodules
2019-05-15 | GSE116074 | GEO
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
Project description:BackgroundHuman epidermal growth factor receptor 2 (HER2) targeted antibodies in combination with chemotherapy has improved outcomes of HER2 positive (pos) breast cancer (BC) but toxicity of therapy remains a problem. High levels of tumor-infiltrating lymphocytes are associated with increased pathologic complete responses for patients treated with neoadjuvant therapy. Here we sought to investigate whether delivery of intratumoral (i.t.) multiepitope major histocompatibility complex (MHC) class II HER2 peptides-pulsed type I polarized dendritic cells (HER2-DC1) in combination with anti-HER2 antibodies without chemotherapy could enhance tumor regression by increasing anti-HER2 lymphocyte infiltration into the tumor.MethodsBALB/c mice bearing orthotopic TUBO tumors, BALB/c mice bearing subcutaneous (s.c.) CT26 hHER2 tumors, or BALB-HER2/neu transgenic mice were all treated with i.t. or s.c. HER2-DC1, anti-HER2 antibodies, paclitaxel, T-DM1 or in combination. Immune response, host immune cells and effector function were analyzed using flow cytometry, interferon-γ ELISA and cytokine/chemokine arrays. The contributions of CD4+ and CD8+ T cells and antibody dependent cellular cytotoxicity (ADCC) were assessed using depleting antibodies and FcγR KO mice. Molecular changes were evaluated by immunohistochemistry and western blot.ResultsHER2-DC1 combined with anti-HER2 antibodies delivered i.t. compared to s.c. induced complete tumor regression in 75-80% of treated mice, with increased tumor infiltrating CD4+ and CD8+ T, B, natural killer T cells (NKT) and natural killer cells, and strong anti-HER2 responses in all HER2pos BC models tested. The therapy caused regression of untreated distant tumors. Labeled HER2-DC1 migrated prominently into the distant tumor and induced infiltration of various DC subsets into tumors. HER2-DC1 i.t. combined with anti-HER2 antibodies displayed superior antitumor response compared to standard chemotherapy with anti-HER2 antibodies. Lasting immunity was attained which prevented secondary tumor formation. The presence of CD4+ and CD8+ T cells and ADCC were required for complete tumor regression. In the HER2pos BC models, HER2-DC1 i.t. combined with anti-HER2 antibodies effectively diminished activation of HER2-mediated oncogenic signaling pathways.ConclusionsHER2-DC1 i.t. with anti-HER2 antibodies mediates tumor regression through combined activation of T and B cell compartments and provides evidence that HER2-DC1 i.t. in combination with anti-HER2 antibodies can be tested as an effective alternative therapeutic strategy to current chemotherapy and anti-HER2 antibodies in HER2pos BC.
| S-EPMC9204433 | biostudies-literature
Project description:We designed a novel intratumoral (IT) IL-12 mRNA therapy to promote local IL-12 tumor production whilst mitigating systemic effects. A single IT dose of mouse (m)IL-12 mRNA induced IFNγ and CD8+ T cell-dependent tumor regression in multiple syngeneic mouse models including MC38-R, and animals with a complete response demonstrated immunity to re-challenge. In order to further investigate the impact of mIL-12 mRNA on the MC38-R TME, we performed tumor transcriptomic evaluation 24h and 7 days after a single IT dose of 0.5 micrograms IL-12 or control mRNA. mRNA was isolated from snap-frozen syngeneic tumors using an RNeasy mini kit (Qiagen) and quantified on the Affymetrix mouse 430 2.0 microarray.
2020-09-01 | E-MTAB-9316 | biostudies-arrayexpress
Project description:We report here a phase I trial (NCT02208362) evaluating locoregional delivery of IL13Rα2-targeted CAR T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were to evaluate safety and feasibility, and secondary objectives were to assess therapy-related cytokine dynamics, CAR T cell persistence and clinical outcomes. Feasibility and safety were established for three routes of locoregional CAR T cell administration [intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV], with IL13Rα2-CAR T cells being well-tolerated with clinically manageable adverse events at all dose levels. Stable disease or better was achieved in 50% of patients, with two partial responses, one complete response (CR), and a second CR after additional CAR T cycles off protocol therapy. Patients with rGBM treated on Arm 5, utilizing dual ICT/ICV delivery and an optimized manufacturing process exhibited the best overall survival of 10.2 months. . Central nervous system (CNS) increases in inflammatory cytokines, including IFNγ, CXCL9, and CXCL10, were associated with CAR T cell administration and bioactivity. Further, pre-treatment intratumoral CD3 T cell levels were positively associated with survival, suggesting an interplay between host immunity and CAR T cells as a determinant of outcomes. These findings advance our understanding of CAR T cell immunotherapy for malignant brain tumors. ClinicalTrials.gov Identifier: NCT02208362
2024-02-20 | GSE255850 | GEO
Project description:Here, using the mouse KRT19-deficient (sgKRT19-edited) PDA model, we find that intratumoral accumulation of natural killer T (NKT) cells are required to establish an immunologically active TME. Mechanistically, intratumoral NKT cells facilitate type I interferon (IFN) production to initiate an anti-tumor adaptive immune response, and orchestrate the intratumoral infiltration of T cells, dendritic cells, natural killer cells and myeloid-derived suppressor cells. At the molecular level, NKT cells promote the production of type I IFN through the interaction of their CD40L with CD40 on myeloid cells. To evaluate the theraputical potential of these observations, we find that administration of folinic acid to mice bearing PDA increases NKT cells in the TME and improves their response to anti-PD-1 antibody treatment. In conclusion, NKT cells have an essential role in the immune response to mouse PDA and are potential targets for immunotherapy.
2024-07-07 | GSE270858 | GEO