Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Low Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

ABSTRACT: The development of approaches for inflaming cold tumors is critical for increasing response to immunotherapy. Here we report that low-dose radiotherapy (LDRT) in mice promotes tumor T-cell inflammation and enables responsiveness to combinatorial immunotherapyin an interferon-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity, and depended on both cytotoxic CD4+and CD8+T cells. LDRTinduced predominantly CD4+cells which exhibited features of exhausted effector and cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, and a novel subset of dendritic cells with activated phenotype that expressed the NKG2D ligand Rae1. Finally, tumor immune rejection was critically dependent on the NKG2D pathway. We translated these findings toa phase I clinical trial. Like in mice, combinatorial treatmenttriggered peripheral T-cell mobilization and resulted in important tumor T-cell infiltration, predominantly of CD4+cells and with Th1 signatures, observed only in patients with immune desert tumors who responded to a novel combination of LDRT, low dose cyclophosphamide and immune checkpoint blockade therapy.These results suggest the novel possibility of rationally combining LDRT with immune checkpoint therapy for the treatment of cold tumors, based on the simultaneous activation of antitumoral innate and adaptive immunity

ORGANISM(S): Homo sapiens

PROVIDER: GSE165612 | GEO | 2021/08/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Metronomic Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

Project description:The development of approaches for inflaming cold tumors is critical for increasing response to immunotherapy (IMT) reliant upon the re-invigoration of T cells for tumor control. Here we report, in a pre-clinical advanced ID8 ovarian cancer model, that metronomic low-dose radiotherapy (LDRT; 1 Gy) promotes T-cell infiltration and enables responsiveness to treatment including low-dose cyclophosphamide (CP), and combinatorial IMT comprising immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4, and anti-CD40 agonist antibody, for significant tumor control and survival. Responses to this radio-combinatorial immunotherapy (RACIM) relied upon re-programming of both innate and adaptive immunity. We further identified RACIM-induced intratumoral dendritic cell states with co-stimulatory capacity and expressing the stress ligand RAE1, as well as of polyfunctional NKG2D+TCF1-PD1+CD4+T cells. We further report major tumor regressions in a subset of advanced cancer patients for which cold tumors were treated with LDRT, CP, aspirin, and ICB (NCT03728179). Unbiased analyses of biopsies revealed T-cell infiltration, up-regulation of type I IFN, and Th1 signatures as well as down-regulation of M2 macrophage and epithelial to mesenchymal transition gene-signatures, and a more oligoclonal TCR repertoire after RACIM, in responding patients.

2021-08-16 | GSE166303 | GEO

Expression data from human memory CD4 T-cells stimulated with autologous monocytes pulsed with HCMV

Project description:The present study reports an unbiased analysis of the genetic profile and regulation of NKG2D expressing CD4 T-cells.An Affymetrix microarray analysis was used to explore the genetic profile of NKG2D+ versus NKG2D- CD4 T-cells. The genetic profile was studied by single gene analysis and gene set enrichment analysis. I found that several immune regulatory receptors was regulated differently in NKG2D+ versus NKG2D- CD4 T-cells. Futhermore, I found that NKG2D+ CD4 T-cells display a genetic profile of cytotoxic T-cells. The gene set enrichment analysis revealed a change in 19 processes, including ARF GTPase activator activity; RNA splicing; Signal transduction; Interspecies interaction between organisms; Regulation of ARF GTPase activity; Cell motility; Mitosis; Cell cycle; Anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolic process; Induction of apoptosis by extracellular signals; Negative regulation of apoptosis; mRNA export from nucleus; Positive regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle; Cell division; Protein polymerization; Spliceosome assembly; Microtubule-based movement; Immune response; mRNA processing. Human CD4 T-cells were isolated from buffy coat by anti-CD4 conjugated magnetic beads. Memory CD4 T-cells were sorted, labeled with CFSE and stimulated with autologous monocytes pulsed with HCMV. HCMV stimulated CD4 T-cells were sorted as CFSE-NKG2D+ or CFSE-NKG2D- and processed for microarray analysis.

2012-08-14 | E-GEOD-33670 | biostudies-arrayexpress

Expression data from human memory CD4 T-cells stimulated with autologous monocytes pulsed with HCMV

2012-08-15 | GSE33670 | GEO

RNA-seq of pancreatic mouse tumor cell lines

2021-11-29 | E-MTAB-11187 | biostudies-arrayexpress

Single cell RNA-seq of pancreatic mouse tumors upon treatment

2021-11-13 | E-MTAB-9954 | biostudies-arrayexpress

Combining targeting of the cancer-metabolome with cancer-associated stress antigens impacts transcriptomic heterogeneity, dynamics, and efficacy of engineered T-cells

Project description:The majority of cancers cannot be efficiently targeted with engineered T cell strategies. In this line, we explored how and whether γδTCR-mediated cancer metabolome targeting can be combined with the attack of cancer-associated stress antigens, like NKG2D-ligands, in order to overcome limited targeting of many tumors, and at the same time skew heterogeneous transcriptomic signatures of engineered immune cells towards more active, and less exhausted phenotypes.Single cell transcriptomic analysis revealed that only NKG2D-4-1BBCD28TM chimera reprogrammed TEGs significantly, by skewing CD4+ TEG heterogeneity towards more adhesive, proliferative, cytotoxic, and less exhausted transcriptional signatures.

2023-09-27 | GSE244053 | GEO

RNA-seq analysis of αPD-1 treatment outcomes in IL-34 expressing or not expressing CT26 cell line

Project description:Interleukin-34 (IL-34) is an alternative ligand to colony-stimulating factor-1 (CSF-1) for the CSF-1 receptor that acts as a key regulator of monocyte/macrophage lineage. In this study, we show that cancer cells-derived IL-34 mediates resistance to immune checkpoint blockade regardless of CSF-1 existence. In a therapeutic study of a programmed death-1 and cytotoxic T-lymphocyte-associated antigen-4 blocking monoclonal antibody, the expression of IL-34 in tumors was accompanied with limited benefits compared to IL-34 non-expressing tumors in various murine cancer models. Consistent with its immunosuppressive characteristics, the expression of IL-34 in tumors correlates with decreased frequencies of cellular (such as CD8+ and CD4+ T cells) and molecular (including various cytokines and chemokines) effectors at the tumor microenvironment. In addition, IL-34 blockade expands the M1-macrophage population. Then, a neutralizing antibody against IL-34 helped to reverse these effects and improved the therapeutic effects of the immune checkpoint blockade in combinatorial therapeutic models, including a patient-derived xenograft model of primary lung adenocarcinoma. Collectively, we revealed that tumor-derived IL-34 inhibits the efficacy of immune checkpoint blockade and proposed the utility of IL-34 blockade as a new strategy for cancer therapy.

2020-09-30 | GSE157602 | GEO

Human CD4 cytotoxic T lymphocytes mediate potent tumor control via tumor cell HLA 2 class II expression in a humanized immune system mouse model

Project description:Efficacy of immune checkpoint inhibitors in cancer can be limited by dysfunction of CD8 T cells or down-regulation of HLA class I. Tumor control mechanisms independent of the CD8/HLA-I axis would bypass these limitations. CD4 cytotoxic T lymphocytes (CTLs) have been detected in diverse human cancers. However, their independent roles in tumor immunity are underexplored. Here, we report CD4 T cell-dependent spontaneous tumor regression and subsequent memory responses in a humanized immune system (HIS) mouse model. HT-29 tumors, which upregulate HLA class II expression in response to IFN-γ, regressed or were eliminated in a subset of tumor implanted HIS mice. Mice with regressing tumors showed increased cytotoxic CD4 T cells in blood and tumors and enhanced HLA-II expression on tumor cells compared to mice with progressing tumors. The intratumoral CD4 T cell subset associated with tumor regression expressed multiple cytotoxic markers and exhibited clonal expansion. Notably, tumor control was abrogated by depletion of CD4 but not CD8 T cells. CD4 T cells derived from tumor-regressing mice exhibited HLA-II-dependent and tumor cell-specific killing ex vivo. Taken together, our study demonstrates a critical role of human CD4 CTLs in mediating potent tumor control independent of CD8 T cells and provides a novel platform to study human CD4 CTL-mediated anti-tumor immunity.

2023-01-22 | GSE223026 | GEO

Combinatorial high throughput drug screening identifies a synergistic drug interaction that sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade

Project description:KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted therapies, immune checkpoint blockade and engineered T cells. Here, we performed a systematic high throughput combinatorial drug screen and identified a synergistic interaction between the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib. This interaction targets KRAS-directed oncogenic signaling in the aggressive and therapy resistant non-glandular mesenchymal subtype of PDAC, driven by an allelic imbalance, increased gene-dosage and expression of oncogenic KRAS. Mechanistically, the combinatorial treatment induces cell cycle arrest and cell death and initiates an interferon response. Using single cell RNA sequencing and immunophenotyping, we show that the combination therapy reprograms the immunosuppressive microenvironment and primes cytotoxic and memory T cells to infiltrate the tumors, thereby sensitizing mesenchymal PDAC to PD-L1 inhibition. This work opens new avenues to target the therapy refractory mesenchymal PDAC subtype.

2022-02-23 | PXD023267 | Pride

Combinatorial high throughput drug screening identifies a synergistic drug interaction that sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade

2022-02-11 | PXD027877 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data