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Project description:Anti-CSF-1R treatment results in rapid regression of murne proneural glioblastoma models. However, the microenvironment response to treatment results in fibrosis that can promote tumor recurrence. We investigated the single-cell transcriptional profile of murine glioblastomas before and after treatment with an anti-CSF-1R inhibitor to determine the cause of fibrotic treatment response.
2024-08-10 | GSE266969 | GEO
Project description:Spatial and scRNAseq profiling of murine glioblastomas treated with and without anti-CSF-1R inhibitors
| PRJNA1108852 | ENA
Project description:Anti-CSF-1R treatment results in rapid regression of murne proneural glioblastoma models. However, the microenvironment response to treatment results in fibrosis that can promote tumor recurrence. We investigated the single-cell transcriptional profile of murine glioblastomas before and after treatment with an anti-CSF-1R inhibitor to determine the cause of fibrotic treatment response.
2024-08-10 | GSE229409 | GEO
Project description:Spatial transcriptomics profile at single cell level of murine glioblastomas treated with and without anti-CSF-1R inhibitors.
| PRJNA1108863 | ENA
Project description:Gene expression profile at single cell level of murine glioblastomas treated with and without anti-CSF-1R inhibitors
| PRJNA954378 | ENA
Project description:BACKGROUND:The pancreatic cancer vaccine, GVAX, induces novel lymphoid aggregates in the otherwise immune quiescent pancreatic ductal adenocarcinoma (PDAC). GVAX also upregulates the PD-1/PD-L1 pathway, and a pre-clinical model demonstrated the anti-tumor effects of combination GVAX and anti-PD-1 antibody therapy (GVAX/?PD-1). Resistance to GVAX was associated with an immune-suppressive myeloid cell infiltration, which may limit further therapeutic gains of GVAX/?PD-1 therapy. The expression of CSF-1R, a receptor important for myeloid cell migration, differentiation and survival, and the effect of its therapeutic blockade in the context of GVAX in PDAC has not been investigated. METHODS:Lymphoid aggregates appreciated in 24 surgically resected PDAC from patients who received one dose of neoadjuvant GVAX were analyzed with multiplex immunohistochemistry. Flow cytometry analysis of tumor infiltrating T-cells in a murine model of PDAC was performed to investigate the therapeutic effects and mechanism of anti-CSF-1R/anti-PD-1/GVAX combination immunotherapy. RESULTS:High CSF-1R expression in resected PDAC from patients who received neoadjuvant GVAX was associated with a higher myeloid to lymphoid cell ratio (p?<?0.05), which has been associated with poorer survival. This higher CSF-1R expression was associated with a higher intra-tumoral infiltration of immature dendritic cells (p?<?0.05), but not mature dendritic cells (p?=?0.132). In the pre-clinical murine model, administering anti-CSF-1R antibody prior to and after GVAX/?PD-1 ("pre/post-?CSF-1R + ?PD-1 + GVAX") enhanced the survival rate compared to GVAX/?PD-1 dual therapy (p?=?0.005), but administering anti-CSF-1R only before GVAX/?PD-1 did not (p?=?0.41). The "pre/post-?CSF-1R?+??PD-1?+?GVAX" group also had higher intra-tumoral infiltration of PD-1?+?CD8+ and PD-1?+?CD4+ T-cells compared to ?PD-1/GVAX (p?<?0.001). Furthermore, this regimen increased the intra-tumoral infiltration of PD-1?+?CD137?+?CD8+, PD-1?+?CD137?+?CD4+ and PD-1?+?OX40?+?CD4+ T-cells (p?<?0.001). These PD-1?+?CD137?+?CD8+ T-cells expressed high levels of interferon-? (median 80-90%) in response to stimulation with CD3/CD28 activation beads, and this expression was higher than that of PD-1?+?CD137-CD8+ T-cells (p?<?0.001). CONCLUSIONS:The conversion of exhausted PD-1+ T-cells to CD137+ activated effector T-cells may contribute to the anti-tumor effects of the anti-CSF-1R/anti-PD-1/GVAX combination therapy. Anti-CSF-1R antibody with anti-PD-1 antibody and GVAX have the potential be an effective therapeutic strategy for treatment of PDAC.
| S-EPMC6234697 | biostudies-literature
Project description:BackgroundColony stimulating factor 1 receptor (CSF-1R) is a single channel III transmembrane receptor tyrosine kinase (RTK) and plays an important role in immune regulation and the development of various cancer types. The expression of CSF-1R in colon adenocarcinoma (COAD) and its prognostic value remain incompletely understood. Therefore, we aim to explore the prognostic value of CSF-1R in COAD and its relationship with tumor immunity.MethodsCSF-1R expression in a COAD cohort containing 103 patients was examined using immunohistochemistry (IHC). The relationship between CSF-1R expression and clinicopathological parameters and prognosis was evaluated. Dual immunofluorescence staining was conducted to determine the localization of CSF-1R in COAD tissues. Univariate and multivariate Cox regression analysis were performed to evaluate independent prognostic factors. Transcriptomic profiles of CSF-1Rhigh and CSF-1Rlow tumor-associated macrophages (TAMs) were investigated. Gene enrichment analysis was used to explore the signal pathways related to CSF-1R. In addition, the relationship between CSF-1R in tumor microenvironment (TME) and tumor immunity was also studied.ResultsIHC analysis showed that CSF-1R was overexpressed in COAD, and higher expression was associated with shorter overall survival (OS). Immunofluorescence staining showed that CSF-1R was co-localized with macrophage marker CD68. Univariate and multivariate Cox regression analysis showed that CSF-1R was an independent prognostic factor for COAD. The results of gene enrichment analysis showed that CSF-1R was involved in tumor immune response and regulation of TME. In addition, CSF-1R was significantly correlated with TME, immune cell infiltration, TMB, MSI, Neoantigen, and immune checkpoint molecules.ConclusionCSF-1R can serve as an independent prognostic factor of COAD and promising immunotherapeutic target of COAD.
| S-EPMC9014714 | biostudies-literature
Project description:Treatment of glioblastoma with anti-CSF-1R immunotherapy, radiotherapy, or surgical tumor resection were found to all induce a fibrotic response to treatment, which was highly associated with tumor recurrence. To investigate the drivers of fibrotic treatment response we performed multi-omic analysis of the glioblastoma microenvironment following treatment with anti-CSF-1R immunotherapy. Studies consisted of mass spectrometry proteomic analysis, single cell transcriptomics, and high-dimensional spatial analysis. These data identified a protective spatial niche that supported tumor cell survival following treatment, ultimately leading to tumor recurrence. Therapeutic inhibition of fibrotic treatment response blocked the formation of this niche, and significantly improved survival in anti-CSF-1R preclinical trials
2024-08-12 | PXD041689 | Pride
Project description:Cerebrovascular pathologies occur in up to 80% of cases of Alzheimer's disease; however, the underlying mechanisms that lead to perivascular pathology and accompanying blood-brain barrier (BBB) disruption are still not fully understood. We have identified previously unreported mutations in colony stimulating factor-1 receptor (CSF-1R) in an ultra-rare autosomal dominant condition termed adult-onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP). Cerebrovascular pathologies such as cerebral amyloid angiopathy (CAA) and perivascular p-Tau were some of the primary neuropathological features of this condition. We have identified two families with different dominant acting alleles with variants located in the kinase region of the CSF-1R gene, which confer a lack of kinase activity and signalling. The protein product of this gene acts as the receptor for 2 cognate ligands, namely colony stimulating factor-1 (CSF-1) and interleukin-34 (IL-34). Here, we show that depletion in CSF-1R signalling induces BBB disruption and decreases the phagocytic capacity of peripheral macrophages but not microglia. CSF-1R signalling appears to be critical for macrophage and microglial activation, and macrophage localisation to amyloid appears reduced following the induction of Csf-1r heterozygosity in macrophages. Finally, we show that endothelial/microglial crosstalk and concomitant attenuation of CSF-1R signalling causes re-modelling of BBB-associated tight junctions and suggest that regulating BBB integrity and systemic macrophage recruitment to the brain may be therapeutically relevant in ALSP and other Alzheimer's-like dementias.
| S-EPMC7863388 | biostudies-literature
Project description:Immunotherapy based on the immune checkpoint blockade has emerged as the most promising approach for cancer therapy. However, the proportion of colorectal cancer patients who benefit from immunotherapy is small due to the immunosuppressive tumor microenvironment. Hence, combination immunotherapy is an ideal strategy to overcome this limitation. In this study, we developed a novel combination of CSF-1R (colony-stimulating factor 1 receptor) inhibitor (PLX3397), oncolytic viruses, and anti-PD-1 antibody. Our results demonstrated that the triple treatment synergistically conferred significant tumor control and prolonged the survival of mouse models of colon cancer. Approximately 43% and 82% of mice bearing the CT26 and MC38 tumor, respectively, survived long term following the triple treatment. This combination therapy reprogrammed the immunosuppressive tumor microenvironment toward a CD8+ T cell-biased anti-tumor immunity by increasing T cell infiltration in the tumor and augmenting anti-tumor CD8+ T cell function. Our results provide a robust strategy for clinical combination therapy.
| S-EPMC6319306 | biostudies-literature