Browse
Submit Data
Databases
API
Help

Dataset Information

31 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Myeloid cell-based delivery of IFN-γ reprograms the leukemia microenvironment and induces anti-tumoral immune responses.

ABSTRACT: The immunosuppressive microenvironment surrounding tumor cells represents a key cause of treatment failure. Therefore, immunotherapies aimed at reprogramming the immune system have largely spread in the past years. We employed gene transfer into hematopoietic stem and progenitor cells to selectively express anti-tumoral cytokines in tumor-infiltrating monocytes/macrophages. We show that interferon-γ (IFN-γ) reduced tumor progression in mouse models of B-cell acute lymphoblastic leukemia (B-ALL) and colorectal carcinoma (MC38). Its activity depended on the immune system's capacity to respond to IFN-γ and drove the counter-selection of leukemia cells expressing surrogate antigens. Gene-based IFN-γ delivery induced antigen presentation in the myeloid compartment and on leukemia cells, leading to a wave of T cell recruitment and activation, with enhanced clonal expansion of cytotoxic CD8⁺ T lymphocytes. The activity of IFN-γ was further enhanced by either co-delivery of tumor necrosis factor-α (TNF-α) or by drugs blocking immunosuppressive escape pathways, with the potential to obtain durable responses.

SUBMITTER: Mucci A

PROVIDER: S-EPMC8495462 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Myeloid cell-based delivery of IFN-γ reprograms leukemia microenvironment and induces anti-tumoral immune responses

Project description:The immunosuppressive microenvironment surrounding tumor cells represents a key cause of treatment failure. Therefore, immunotherapies aimed at reprogramming the immune system have largely spread in the past years. We employed gene transfer into hematopoietic stem and progenitor cells to selectively express anti-tumoral cytokines in tumor-infiltrating monocytes/macrophages. We show that Interferon-γ (IFNγ) reduced tumor progression in mouse models of B-cell acute lymphoblastic leukemia (B-ALL) and colorectal carcinoma (MC38). Its activity was dependent on the capacity of the immune system to respond to IFNγ and drove counter-selection of leukemia cells expressing surrogate antigens. Gene-based IFNγ delivery induced antigen presentation in the myeloid compartment and on leukemia cells, leading to a wave of T cell recruitment and activation, with enhanced clonal expansion of cytotoxic CD8+ T lymphocytes. The activity of IFNγ was further enhanced by either co-delivery of tumor necrosis factor α (TNFα) or by drugs blocking immunosuppressive escape pathways, with the potential to obtain durable responses.

2021-08-23 | GSE178941 | GEO

Myeloid cell-based delivery of IFN-γ reprograms leukemia microenvironment and induces anti-tumoral immune responses

Project description:Myeloid cell-based delivery of IFN-γ reprograms leukemia microenvironment and induces anti-tumoral immune responses

| PRJNA741522 | ENA

IFN-γ-STAT1-iNOS Induces Myeloid Progenitors to Acquire Immunosuppressive Activity.

Project description:Autoimmune diseases often induce dysregulated hematopoiesis with altered number and function of hematopoietic stem and progenitor cells (HSPCs). However, there are limited studies on the direct regulation of HSPCs on T cells, which are often detrimental to autoimmunity. Here, we found that in a murine model of Concanavalin A-induced autoimmune hepatitis, LSK (Lineage-Sca-1+c-Kit+)-like cells accumulated in liver, spleen, and bone marrow (BM), which were myeloid progenitors (Lineage-Sca-1-c-Kit+) that upregulated Sca-1 expression upon T cell-derived IFN-γ stimulation. Strikingly, BM LSK-like cells from mice induced by Con A to develop autoimmune hepatitis or alternatively myeloid progenitors from wild-type mice possessed strong in vitro suppressive ability. Their suppressive function depended on T cell-derived IFN-γ in a paracrine fashion, which induced STAT1 phosphorylation, inducible nitric oxide synthase expression, and nitric oxide production. Blocking IFN-γ/IFN-γ receptor interaction, knockout of STAT1, or iNOS inhibition abrogated their suppressive function. In addition, the suppressive function was independent of differentiation; mitomycin C-treated myeloid progenitors maintained T cell suppressive ability in vitro. Our data demonstrate a mechanism of inflammation induced suppressive function of myeloid progenitors, which may participate directly in suppressing T cell-mediated immunopathology.

| S-EPMC5614959 | biostudies-literature

Concomitant type I IFN and M-CSF signaling reprograms monocyte differentiation and drives pro-tumoral arginase production.

Project description:BackgroundType I IFN-based therapies against solid malignancies have yielded only limited success. How IFN affects tumor-associated macrophage (TAM) compartment to impact the therapeutic outcomes are not well understood.MethodsThe effect of an IFN-inducer poly(I:C) on tumor-infiltrating monocytes and TAMs were analyzed using a transplantable mouse tumor model (LLC). In vitro culture systems were utilized to study the direct actions by poly(I:C)-IFN on differentiating monocytes.ResultsWe found that poly(I:C)-induced IFN targets Ly6C+ monocytes and impedes their transition into TAMs. Such an effect involves miR-155-mediated suppression of M-CSF receptor expression, contributing to restricting tumor growth. Remarkably, further analyses of gene expression profile of IFN-treated differentiating monocytes reveal a strong induction of Arg1 (encoding arginase-1) in addition to other classical IFN targets. Mechanistically, the unexpected Arg1 arm of IFN action is mediated by a prolonged STAT3 signaling in monocytes, in conjunction with elevated macrophage colony-stimulating factor (M-CSF) signaling. Functionally, induction of ARG1 limited the therapeutic effect of IFN, as inhibition of arginase activity could strongly synergize with poly(I:C) to enhance CD8+ T cell responses to thwart tumor growth in mice.ConclusionsTaken together, we have uncovered two functionally opposing actions by IFN on the TAM compartment. Our work provides significant new insights on IFN-mediated immunoregulation that may have implications in cancer therapies.

| S-EPMC6354658 | biostudies-literature

Acute myeloid leukemia induces protumoral p16INK4a-driven senescence in the bone marrow microenvironment.

Project description:Acute myeloid leukemia (AML) is an age-related disease that is highly dependent on the bone marrow (BM) microenvironment. With increasing age, tissues accumulate senescent cells, characterized by an irreversible arrest of cell proliferation and the secretion of a set of proinflammatory cytokines, chemokines, and growth factors, collectively known as the senescence-associated secretory phenotype (SASP). Here, we report that AML blasts induce a senescent phenotype in the stromal cells within the BM microenvironment and that the BM stromal cell senescence is driven by p16INK4a expression. The p16INK4a-expressing senescent stromal cells then feed back to promote AML blast survival and proliferation via the SASP. Importantly, selective elimination of p16INK4a+ senescent BM stromal cells in vivo improved the survival of mice with leukemia. Next, we find that the leukemia-driven senescent tumor microenvironment is caused by AML-induced NOX2-derived superoxide. Finally, using the p16-3MR mouse model, we show that by targeting NOX2 we reduced BM stromal cell senescence and consequently reduced AML proliferation. Together, these data identify leukemia-generated NOX2-derived superoxide as a driver of protumoral p16INK4a-dependent senescence in BM stromal cells. Our findings reveal the importance of a senescent microenvironment for the pathophysiology of leukemia. These data now open the door to investigate drugs that specifically target the "benign" senescent cells that surround and support AML.

| S-EPMC6356984 | biostudies-literature

IFNα induces prolonged remissions modeling curative immunologic responses in chronic myeloid leukemia.

Project description:Tyrosine kinase inhibitor therapy has dramatically changed the outcome of chronic myeloid leukemia (CML) patients. However, the treatment is not considered to be curative and may present deleterious side effects, such that additional therapy options are warranted. Here, we discuss the beneficial immunomodulatory effects of interferon α (IFNα) therapy and the immunological changes related to optimal treatment responses.

| S-EPMC4063137 | biostudies-literature

IFN-γ and tumor gangliosides: Implications for the tumor microenvironment.

Project description:Gangliosides shed by tumors into their microenvironment (TME) are immunoinhibitory. Interferon-γ (IFN-γ) may boost antitumor immune responses. Thus we wondered whether IFN-γ would counteract tumor ganglioside-mediated immune suppression. To test this hypothesis, we exposed human monocyte-derived LPS-activated dendritic cells (DC) to IFN-γ and to a highly purified ganglioside, GD1a. DC ganglioside exposure decreased TLR-dependent p38 signaling, explaining the previously observed ganglioside-induced down-modulation of pro-inflammatory surface markers and cytokines. Strikingly, while increasing LPS-dependent DC responses, IFN-γ unexpectedly did not counteract the inhibitory effects of GD1a. Rather, induction of indoleamine 2,3-dioxygenase (IDO1), and expression of STAT1/IRF-1 and programmed cell death ligand (PD-L1), indicated that the immunoinhibitory, not an immune stimulatory, IFN-γ-signaling axis, was active. The combination, IFN-γ and DC ganglioside enrichment, markedly impaired DC stimulatory potential of CD8+ T-cells. We suggest that gangliosides and IFN-γ may act in concert as immunosuppressive mediators in the TME, possibly promoting tumor progression.

| S-EPMC5826801 | biostudies-literature

Gefitinib induces myeloid differentiation of acute myeloid leukemia.

Project description:Cure rates for patients with acute myeloid leukemia (AML) remain low despite ever-increasing dose intensity of cytotoxic therapy. In an effort to identify novel approaches to AML therapy, we recently reported a new method of chemical screening based on the modulation of a gene expression signature of interest. We applied this approach to the discovery of AML-differentiation-promoting compounds. Among the compounds inducing neutrophilic differentiation was DAPH1 (4,5-dianilinophthalimide), previously reported to inhibit epidermal growth factor receptor (EGFR) kinase activity. Here we report that the Food and Drug Administration (FDA)-approved EGFR inhibitor gefitinib similarly promotes the differentiation of AML cell lines and primary patient-derived AML blasts in vitro. Gefitinib induced differentiation based on morphologic assessment, nitro-blue tetrazolium reduction, cell-surface markers, genome-wide patterns of gene expression, and inhibition of proliferation at clinically achievable doses. Importantly, EGFR expression was not detected in AML cells, indicating that gefitinib functions through a previously unrecognized EGFR-independent mechanism. These studies indicate that clinical trials testing the efficacy of gefitinib in patients with AML are warranted.

| S-EPMC1895296 | biostudies-literature

Targeting the microenvironment in acute myeloid leukemia.

Project description:The bone marrow microenvironment plays a critical role in the development, progression, and relapse of acute myeloid leukemia (AML). Similar to normal hematopoietic stem cells, AML blasts express receptors on their surface, allowing them to interact with specific components of the marrow microenvironment. These interactions contribute to both chemotherapy resistance and disease relapse. Preclinical studies and early phase clinical trials have demonstrated the potential for targeting the tumor-microenvironment interactions in AML. Agents currently under investigation include hypoxia-inducible agents and inhibitors of CXCR4 and adhesion molecules such as VLA-4 and E-selectin.

| S-EPMC4447552 | biostudies-literature

Adenovirus-Vectored African Swine Fever Virus pp220 Induces Robust Antibody, IFN-γ, and CTL Responses in Pigs.

Project description:African Swine Fever Virus (ASFV) poses a serious threat to the pork industry worldwide; however, there is no safe vaccine or treatment available. The development of an efficacious subunit vaccine will require the identification of protective antigens. The ASFV pp220 polyprotein is essential for virus structural integrity. This polyprotein is processed to generate p5, p34, p14, p37, and p150 individual proteins. Immunization of pigs with a cocktail of adenoviruses expressing the proteins induced significant IgG, IFN-γ-secreting cells, and cytotoxic T lymphocyte responses. Four predicted SLA-I binding nonamer peptides, namely p34161-169, p37859-867, p1501363-1371, and p1501463-1471, recalled strong IFN-γ+ PBMC and splenocyte responses. Notably, peptide p34161-169 was recognized by PBMCs isolated from 7/10 pigs and by splenocytes isolated from 8/10 pigs. Peptides p37859-867 and p1501363-1371 stimulated recall IFN-γ+ responses in PBMCs and splenocytes isolated from 8/10 pigs, whereas peptide p1501463-1471 recalled responses in PBMCs and splenocytes isolated from 7/10 to 9/10 pigs, respectively. The results demonstrate that the pp220 polyprotein contains multiple epitopes that induce robust immune responses in pigs. Importantly, these epitopes are 100% conserved among different ASFV genotypes and were predicted to bind multiple SLA-I alleles. The outcomes suggest that pp220 is a promising candidate for inclusion in a prototype subunit vaccine.

| S-EPMC9195138 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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