Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Bexmarilimab activates human tumor-associated macrophages to support adaptive immune responses in interferon-poor immune microenvironments

ABSTRACT: Immune checkpoint inhibitors (ICI) show substantially greater efficacy in inflamed tumors characterized by preexisting T-cell infiltration and IFN signaling than in noninflamed “cold” tumors, which often remain immunotherapy resistant. The cancer immunotherapy bexmarilimab, which inhibits the scavenger receptor Clever-1 to release macrophage immunosuppression and activate adaptive immunity, has shown treatment benefit in subsets of patients with advanced solid malignancies. However, the mechanisms that determine bexmarilimab therapy outcome in individual patients are unknown. Here we characterized bexmarilimab response in ovarian cancer ascites macrophages ex vivo using single-cell RNA-sequencing and demonstrated increased IFN signaling and CXCL10 secretion following bexmarilimab treatment. We further showed that bexmarilimab was most efficacious in macrophages with low baseline IFN signaling, as chronic IFNγ priming abolished bexmarilimab-induced TNFα release. These results highlight an approach to target immunologically cold tumors and to increase the likelihood of their subsequent response to ICIs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222649 | GEO | 2023/10/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Monocyte vs Macrophage Study

Project description:Human intestinal macrophages contribute to tissue homeostasis in noninflamed mucosa through profound down-regulation of pro-inflammatory cytokine release. Here, we show that this down-regulation extends to Toll-like receptor (TLR)-induced cytokine release, as intestinal macrophages expressed TLR3-TLR9 but did not release cytokines in response to TLR-specific ligands. Likely contributing to this unique functional profile, intestinal macrophages expressed markedly down-regulated adapter proteins MyD88 and Toll interleukin receptor 1 domain-containing adapter-inducing interferon beta, which together mediate all TLR MyD88-dependent and -independent NF-kappaB signaling, did not phosphorylate NF-kappaB p65 or Smad-induced IkappaBalpha, and did not translocate NF-kappaB into the nucleus. Importantly, transforming growth factor-beta released from intestinal extracellular matrix (stroma) induced identical down-regulation in the NF-kappaB signaling and function of blood monocytes, the exclusive source of intestinal macrophages. Our findings implicate stromal transforming growth factor-beta-induced dysregulation of NF-kappaB proteins and Smad signaling in the differentiation of pro-inflammatory blood monocytes into noninflammatory intestinal macrophages. Comparison of unstimulated monocytes and macrophages, and flagellin stimulated monocytes and macrophages.

2010-07-07 | E-GEOD-22373 | biostudies-arrayexpress

Metronomic Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

Project description:We report major tumor regressions in a subset of advanced cancer patients for which cold tumors were treated with low-dose radiotherapy, cyclophosphamide, 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 radio-combinatorial immunotherapy, in responding patients.

2021-08-16 | GSE167455 | GEO

Monocyte vs Macrophage Study

2010-06-22 | GSE22373 | GEO

XRN1 knockdown in tumor cells stimulates immune cell infiltration

Project description:Despite the remarkable achievement of immune checkpoint blockade (ICB) therapy, the response rate is relatively low and only a subset of patients can benefit from the treatment. We hypothesize that targeting RNA decay machinery may lead to accumulation of aberrantRNA, triggering interferon (IFN) signaling and sensitizing tumor cells to immunotherapy. With this in mind, we identified an RNA exoribonuclease, XRN1 as a potential target. Silencing of XRN1 suppressed tumor growth in syngeneic immunocompetent mice and potentiated immunotherapy, while silencing of XRN1 alone did not affect tumor growth in immune deficient mice. Mechanistically, XRN1 depletion activated interferon signaling and viral defense pathway; both pathways play determinant roles in regulating immune evasion. In murine tumors engrafted on immmunocompetent mice, XRN1 depletion significantly enhanced immune cell infiltration in solid tumors especially in combinatory with PD-1 blockade. We identified aberrant-RNA sensing signaling proteins (RIG-I/MAVS and PKR) in mediating the expression of IFN genes, as depletion of each of them blunted the elevation of anti-viral/IFN signaling in Xrn1 silenced cells. Analysis of pan-cancer CRISPR screening data indicated that IFN signaling triggered by Xrn1 silencing is a common phenomenon, suggesting that the effect of Xrn1 silencing may be extend to multiple types of cancers.

2023-02-21 | GSE202587 | GEO

Proteomics of immune cells from liver tumors reveals immunotherapy targets

Project description:Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer cells, monocyte/macrophages, CD4+ and CD8+ T cells, and NK cells isolated from tumors, liver, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2, typically only found in activated NK cells, is also upregulated in chronically stimulated CD8+ T cells in tumors. Ablation of AFAP1L2 in CD8+ T cells increased their viability upon repeated stimulation and enhanced their antitumor activity synergistically with PD-L1 blockade in mouse models. Our data revealed new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer (www.immunomics.ch/liver).

2023-04-19 | PXD040957 | Pride

Cryoablation reshapes the immune microenvironment in the distal tumor and enhances the anti-tumor immunity

Project description:As one of the local treatments, cryoablation plays an increasingly important role in the comprehensive treatment of malignant tumors with its advantages of less trauma, high reproducibility, and minimally invasive. Activation of anti-tumor immunity, another characteristic of cryoablation, has attracted more and more attention with the extensive application of immunotherapy. Unfortunately, the mechanism by which cryoablation enhances anti-tumor immunity is still unclear. In this study, we used a multi-omics approach to investigate the effects of local cryoablation on the distal tumor microenvironment. In this study, we proved that large amounts of tumor antigens are released post-cryoablation, leading to a sterile inflammatory response in distant tumors. During this period, lysosome-related pathways are activated, resulting in overexpression of SNAP23 and STXBP2, activation of immune effector cells, suppression of the release of immunosuppressive factors, and finally enhancement of anti-tumor immunity. Finally, cryoablation turning “Cold tumors” into “Hot tumors”, which shows a broad prospect in the combined immunotherapy.

2022-08-23 | GSE201590 | GEO

Type I interferon signaling pathway enhances immune-checkpoint inhibition in KRAS mutant lung tumors [LCM]

Project description:Lung cancer is the leading cause of cancer mortality worldwide. KRAS oncogenes are responsible for at least a quarter of lung adenocarcinomas, the main subtype of lung cancer. After four decades of intense research, selective inhibitors of KRAS oncoproteins are finally reaching the clinic. Yet, their effect on overall survival is limited due to the rapid appearance of drug resistance, a likely consequence of the high intratumoral heterogeneity characteristic of these tumors. In this study, we have attempted to identify those functional alterations that result from KRAS oncoprotein expression during the earliest stages of tumor development. Such functional changes are likely to be maintained during the entire process of tumor progression regardless of additional co-occurring mutations. Single-cell RNA sequencing analysis of murine alveolar type 2 cells expressing a resident Kras oncogene revealed impairment of the type I interferon pathway, a feature maintained throughout tumor progression. This alteration was also present in advanced murine and human tumors harboring additional mutations in the p53 or LKB1 tumor suppressors. Restoration of type I interferon (IFN) signaling by IFN-beta or constitutive active stimulator of interferon genes (STING) expression had a profound influence on the tumor microenvironment, switching them from immunologically “cold” to immunologically “hot” tumors. Therefore, enhancement of the type I IFN pathway predisposes KRAS mutant lung tumors to immunotherapy treatments, regardless of co-occurring mutations in p53 or LKB1.

2024-08-12 | GSE274351 | GEO

Intrapleural nano-immunotherapy promotes innate and adaptive immune responses to enhance anti-PD-L1 therapy for malignant pleural effusion

Project description:Malignant pleural effusion (MPE) is indicative of terminal malignancy with uniformly fatal prognosis. Often, two distinct compartments of tumor microenvironment, the effusion and disseminated pleural tumors, co-exist in the pleural cavity, presenting a major challenge for therapeutic interventions and drug delivery. Clinical evidence suggests that MPE comprises abundant tumor associated myeloid cells with the tumor-promoting phenotype, impairing antitumor immunity. Here, we developed liposomal cyclic dinucleotide (LNP-CDN) for targeted activation of STING signaling in macrophages and dendritic cells and showed that, upon intrapleural administration, they induce drastic changes in the transcriptional landscape in MPE, mitigating the immune cold MPE in both the effusion and pleural tumors. Moreover, combination immunotherapy with blockade of PD-L1 potently reduced MPE volume and inhibited tumor growth not only in pleural cavity but also in lung parenchyma, conferring significantly prolonged survival of MPE-bearing mice. Furthermore, the LNP-CDN-induced immunological effects were also observed with clinical MPE samples, suggesting the potential of intrapleural LNP-CDN for clinical MPE immunotherapy.

2021-09-21 | GSE179783 | GEO

Intrapleural nano-immunotherapy promotes innate and adaptive immune responses to enhance anti-PD-L1 therapy for malignant pleural effusion

2021-09-21 | GSE164487 | GEO

Type I interferon signaling pathway enhances immune-checkpoint inhibition in KRAS mutant lung tumors [cell lines]

2024-08-12 | GSE274352 | GEO