Enhancing radiotherapy response via intratumoral injection of the TLR9 agonist CpG to stimulate CD8 T cells in an autochthonous mouse model of sarcoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE252213 | GEO | 2024/01/01
REPOSITORIES: GEO
Similar Datasets
Project description:A single-cell analysis (10x) of p53/MCA induced sarcomas tumors with and without radiation and CpG treatment. p53/MCA induced sarcomes are induced by intramuscular injection of adenovirus expressing Cas9 and sgRNA targeting Trp53 (Adeno-p53-sgRNA; Viraquest) at gastrucnemius muscle site. We used scRNA-seq to analyze the differences in immune cells after treatment with CpG+RT
2024-01-01 | GSE252143 | GEO
Project description:We have designed a novel therapeutic approach for lymphoma that combines targeted kinase inhibition with in situ vaccination. Intratumoral injection of an unmethylated cytosine guanine dinucleotide (CpG)-enriched oligodeoxynucleotide, an agonist for the toll-like receptor 9 (TLR9), induces the activation of natural killer cells, macrophages, and antigen presenting cells that control tumor growth at the local site. Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase, a key enzyme in the signaling pathway downstream of B-cell receptor, is an effective treatment against many types of B-cell lymphomas. The combination of intratumoral injection of CpG with systemic treatment by ibrutinib resulted in eradication of the tumors not only in the injected site, but also at distant sites. Surprisingly, this combinatorial antitumor effect required an intact T-cell immune system since it did not occur in nude, severe combined immunodeficiency, or T-cell depleted mice. Moreover, T cells from animals treated with intratumoral CpG and ibrutinib prevented the outgrowth of newly injected tumors. This result suggests that ibrutinib can induce immunogenic cell death of lymphoma cells and that concomitant stimulation of antigen-presenting cells in the tumor microenvironment by toll-like receptor ligands can lead to a powerful systemic antitumor immune response.
| S-EPMC4375105 | biostudies-literature
Project description:mRNA-seq for expression profiling of Myc and Yap1 activated mouse lung tumors and controls. 4 cohorts of lung tumors induced through nasal instillation of Cre/sgRNA(MS2)-encoding lentivirus in mice carrying conditional P53 loss (P53 F/F), oncogenic Kras (Kras LSL-G12D/+), and CRISPRa/SAM construct (Rosa26(LSL-SAM) or YFP reporter (Rosa26(LSL-YFP): 4 P53(L/L), Kras(LSL-G12D/+), Rosa26(LSL-SAM) / lenti(CMV-Cre/U6-sgRNA(Myc) (PPKS/M); 4 P53(L/L), Kras(LSL-G12D/+), Rosa26(LSL-SAM) / lenti(CMV-Cre/U6-sgRNA(Yap1) (PPKS/Y); 4 P53(L/L), Kras(LSL-G12D/+), Rosa26(LSL-SAM) / lenti(CMV-Cre/U6-sgRNA(non-targeted) (PPKS/NT); 4 P53(L/L), Kras(LSL-G12D/+), Rosa26(LSL-YFP) / lenti(CMV-Cre/U6-sgRNA(non-targeted) (PPKY/NT)
2022-08-30 | E-MTAB-11122 | biostudies-arrayexpress
Project description:We have developed and previously reported on a therapeutic vaccination strategy for indolent B-cell lymphoma that combines local radiation to enhance tumor immunogenicity with the injection into the tumor of a TLR9 agonist. As a result, antitumor CD8(+) T cells are induced, and systemic tumor regression was documented. Because the vaccination occurs in situ, there is no need to manufacture a vaccine product. We have now explored this strategy in a second disease: mycosis fungoides (MF). We treated 15 patients. Clinical responses were assessed at the distant, untreated sites as a measure of systemic antitumor activity. Five clinically meaningful responses were observed. The procedure was well tolerated and adverse effects consisted mostly of mild and transient injection site or flu-like symptoms. The immunized sites showed a significant reduction of CD25(+), Foxp3(+) T cells that could be either MF cells or tissue regulatory T cells and a similar reduction in S100(+), CD1a(+) dendritic cells. There was a trend toward greater reduction of CD25(+) T cells and skin dendritic cells in clinical responders versus nonresponders. Our in situ vaccination strategy is feasible also in MF and the clinical responses that occurred in a subset of patients warrant further study with modifications to augment these therapeutic effects. This study is registered at www.clinicaltrials.gov as NCT00226993.
| S-EPMC3257006 | biostudies-literature
Project description:The tumor environment exerts a powerful suppressive influence on infiltrating tumor-reactive T cells. It induces tolerance of adoptively transferred effector T cells as they enter tumors and maintains the tolerance of persisting tumor-infiltrating T cells. In an autochthonous prostate cancer model, in which tumor-reactive CD8 T cells are trackable, we demonstrate that both depletion of endogenous dendritic cells (DCs) and intratumoral injection of Ag-loaded mature DCs delayed the tolerization of tumor-infiltrating effector CD8 T cells. Intratumoral injection of Ag-loaded DCs also reactivated tolerized CD8 T cells in the tumor tissue. The observed effects lasted as long as the injected DCs persisted. These findings are consistent with a critical role of DCs in modulating T cell reactivity in the tumor environment. They also suggest new potential strategies to extend the functionality of transferred effector T cells and to restore function to tolerized tumor-infiltrating T cells for cancer immunotherapy.
| S-EPMC3061230 | biostudies-literature
Project description:To determine the effect on gene expression of intratumoral injection of the Toll-like receptor agonist CpG1826. MC38 colon cancer cells were injected subcutaneously into C57BL/6 mice and allowed to establish until ~40 mm2.
2009-09-23 | GSE18203 | GEO
Project description:BackgroundComplex tumor and immune microenvironment render pancreatic ductal adenocarcinoma (PDAC) resistant to immune checkpoint inhibitors (ICIs). Therefore, a strategy to convert the immune hostile into an immunopermissive tumor is required. Recent studies showed that intratumoral injection of Toll-like receptor 9 agonist IMO-2125 primes the adaptive immune response. Phase I and II trials with intratumoral IMO-2125 demonstrated its safety and antitumoral activity.MethodsWe generated an array of preclinical models by orthotopically engrafting PDAC-derived cell lines in syngeneic mice and categorized them as high, low and no immunogenic potential, based on the ability of tumor to evoke T lymphocyte or NK cell response. To test the antitumor efficacy of IMO-2125 on locally treated and distant sites, we engrafted cancer cells on both flanks of syngeneic mice and treated them with intratumoral IMO-2125 or vehicle, alone or in combination with anti-PD1 ICI. Tumor tissues and systemic immunity were analyzed by transcriptomic, cytofluorimetric and immunohistochemistry analysis.ResultsWe demonstrated that intratumoral IMO-2125 as single agent triggers immune system response to kill local and distant tumors in a selected high immunogenic subtype affecting tumor growth and mice survival. Remarkably, intratumoral IMO-2125 in combination with systemic anti-PD1 causes a potent antitumor effect on primary injected and distant sites also in pancreatic cancer models with low immunogenic potential, preceded by a transition toward an immunopermissive microenvironment, with increase in tumor-infiltrating dendritic and T cells in tumor and lymph nodes.ConclusionWe demonstrated a potent antitumor activity of IMO-2125 and anti-PD1 combination in immunotherapy-resistant PDAC models through the modulation of immune microenvironment, providing the rationale to translate this strategy into a clinical setting.
| S-EPMC8420705 | biostudies-literature
Project description:Pancreatic adenocarcinoma is an aggressive disease that has poor outcomes despite maximal traditional therapies. Thus, treatment of this cancer demands innovative strategies to be used in addition to standing therapies in order to provide new avenues of care. Here, we describe the technique of using endoscopic ultrasound in order to directly inject both novel and conventional therapies into pancreatic tumors. We detail the rationale behind this strategy and the many benefits it provides. We then describe our technique in detail, including our experience injecting the AdV-tk adenoviral vector to create an in situ vaccine effect.
| S-EPMC3623468 | biostudies-literature
Project description:PurposeTo create and test a multipurpose brachytherapy catheter prototype enabling intratumoral injection and brachytherapy after a single catheter insertion.Methods and materialsThe design of the prototype consists of an outer tube and an inner syringe tube that can be filled with injectable agent. The outer sheath and inner syringe tube were constructed using polytetrafluoroethylene tubing, and the other components were 3D printed using dental resin and polylactic acid material. To demonstrate functionality, we injected in vitro phantoms with dyed saline. For proof of concept, we demonstrated the potential for the prototype to deliver cell therapy, enhance tumor delineation, deliver tattoo ink for pathology marking, avoid toxicity through local delivery of chemotherapy, and facilitate combination brachytherapy and immunotherapy.ResultsThe prototype enables accurate injection in vitro and in vivo without altering dosimetry. To illustrate the potential for delivery of cell therapies, we injected luciferase-expressing splenocytes and confirmed their delivery with bioluminescence imaging. To demonstrate feasibility of radiographically visualizing injected material, we delivered iohexol contrast intratumorally and confirmed tumor retention using Faxitron x-ray imaging. In addition, we show the potential of intratumoral administration to reduce toxicity associated with cyclophosphamide compared with systemic administration. To demonstrate feasibility, we treated tumor-bearing mice with brachytherapy (192Ir source, 2 Gy to 5 mm) in combination with intratumoral injection of 375,000 U of interleukin 2 and observed no increased toxicity.ConclusionsThese results demonstrate that a prototype multipurpose brachytherapy catheter enables accurate intratumoral injection and support the feasibility of combining intratumoral injection with brachytherapy.
| S-EPMC8323107 | biostudies-literature
Project description:The combination of the synthetic TLR9 ligand CpG and agnostic OX40 antibody can trigger systemic antitumor immune responses upon co-injection into the tumor microenvironment, eradicating simultaneous untreated sites of metastatic disease. Here we explore the application of this in situ immunotherapy to the neoadjuvant setting. Current neoadjuvant checkpoint blockade therapy is delivered systemically, resulting in off-target adverse effects. In contrast, intratumoral immunotherapy minimizes the potential for toxicities and allows for greater development of combination therapies. In two metastatic solid tumor models, neoadjuvant intratumoral immunotherapy generated a local T-cell antitumor response that then acted systemically to attack cancer throughout the body. In addition, the importance of timing between neoadjuvant immunotherapy and surgical resection was established, as well as the increased therapeutic power of adding systemic anti-PD1 antibody. The combination of local and systemic immunotherapy generated an additional survival benefit due to synergistic inhibitory effect on tumor-associated macrophages. These results provide a strong rationale for translating this neoadjuvant intratumoral immunotherapy to the clinical setting, especially in conjunction with established checkpoint inhibitors.SignificanceThis work demonstrates the ability of neoadjuvant intratumoral immunotherapy to target local and distant metastatic disease and consequently improve survival.
| S-EPMC8983569 | biostudies-literature