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Project description:Melanoma is one of the solid tumor types with the highest risk of brain metastasis. However, the biology of melanoma brain metastasis and the contribution of the brain immune microenvironment to the responses to therapies remain insufficiently characterized. By using preclinical models and single-cell transcriptomics, we identify microglia, as critical regulators of melanoma biology in the brain. We show that activation of the Rela/NF-kB pathway in microglia promotes melanoma brain metastasis and that targeting this pathway elicits microglia reprogramming towards a pro-inflammatory phenotype that enhances anti-tumor immunity and reduces brain metastatic burden. Additionally, canonical and pro-inflammatory microglial markers in melanoma brain metastasis correlate with better responses to immune checkpoint inhibitors in patients and we show that Rela/NF-kB targeting improves responses to these therapies in the brain. Thus, we propose targeting Rela/NF-kB in activated microglia as a strategy to promote anti-tumor immunity and to improve the response to immune checkpoint inhibitors in melanoma brain metastasis.
2025-02-07 | GSE263622 | GEO
Project description:Melanoma is one of the tumor types with the highest risk of brain metastasis. However, the biology of melanoma brain metastasis and the contribution of the brain immune microenvironment to the responses to therapies remain insufficiently characterized. By using preclinical models and single-cell transcriptomics, we identify a mechanism to promote antitumor immunity in melanoma brain metastasis. We show that activation of the Rela/NF-kB pathway in microglia promotes melanoma brain metastasis and that targeting this pathway elicits microglia reprogramming towards a proinflammatory phenotype that enhances antitumor immunity and reduces brain metastatic burden. Additionally, proinflammatory microglial markers in melanoma brain metastasis correlate with better responses to immune checkpoint inhibitors in patients and we show that Rela/NF-kB targeting improves responses to these therapies in the brain. Thus, we propose targeting Rela/NF-kB in activated microglia as a strategy to promote antitumor immunity and responses to immune checkpoint inhibitors in melanoma brain metastasis.
2025-02-07 | GSE285670 | GEO
Project description:Microglial reprogramming enhances anti-tumor immunity and immunotherapy response in melanoma brain metastases.
| PRJNA1098587 | ENA
Project description:Microglial reprogramming enhances anti-tumor immunity and immunotherapy response in melanoma brain metastases [RNA-seq]
| PRJNA1098589 | ENA
Project description:Microglial reprogramming enhances antitumor immunity and immunotherapy response in melanoma brain metastases
| PRJNA1205401 | ENA
Project description:Melanoma is one of the solid tumor types with the highest risk of brain metastasis. However, the biology of melanoma brain metastasis and the contribution of the brain immune microenvironment to the responses to therapies remain insufficiently characterized. By using preclinical models and single-cell transcriptomics, we identify microglia, as critical regulators of melanoma biology in the brain. We show that activation of the Rela/NF-kB pathway in microglia promotes melanoma brain metastasis and that targeting this pathway elicits microglia reprogramming towards a pro-inflammatory phenotype that enhances anti-tumor immunity and reduces brain metastatic burden. Additionally, canonical and pro-inflammatory microglial markers in melanoma brain metastasis correlate with better responses to immune checkpoint inhibitors in patients and we show that Rela/NF-kB targeting improves responses to these therapies in the brain. Thus, we propose targeting Rela/NF-kB in activated microglia as a strategy to promote anti-tumor immunity and to improve the response to immune checkpoint inhibitors in melanoma brain metastasis.
2025-02-07 | GSE263623 | GEO
Project description:Microglial reprogramming by targeting NF-kB enhances anti-tumor immunity and responses to immunotherapy in melanoma brain metastasis [scRNAseq_Nras-MBM]
| PRJNA1098591 | ENA
Project description:Tumor immunotherapy offers a new paradigm to treat cancer; however, the existing regimens are accompanied by the dilemma of insufficient therapeutic outcomes and off-target adverse effects. The intestinal immune system contains a bulk of immune cells, which can be important contributors to the maintenance of systemic immune homeostasis. However, manipulating intestinal immunity to achieve systemic anti-tumor immunity is extremely challenging. Here, an oral immunotherapy strategy is reported using immune-enhancing fullerenes (IEF) that can reinvigorate anti-tumor immunity via immune cell-metabolic reprogramming of intestinal immune cells. Findings show that IEF can remodel anti-inflammatory macrophages into tumor-killing macrophages by regulating the energy metabolism pathway from oxidative phosphorylation (OXPHOS) to glycolysis. Consequently, IEF can reprogram the immunosuppressive intestinal immunity and enhance sys temic immunity in vivo, thereby boosting anti-tumor immunity and converting "cold" tumors into "hot" tumors. Oral immunotherapy strategy, modulating autoimmune cells in the intestine and achieving systemic anti-tumor immunity, can ensure safe and efficient tumor immunotherapy.
| S-EPMC10724426 | biostudies-literature
Project description:Resistance to checkpoint-blockade treatments is a challenge in the clinic. Both primary and acquired resistance have become major obstacles, greatly limiting the long-lasting effects and wide application of blockade therapy. Many patients with metastatic melanoma eventually require further therapy. The absence of T-cell infiltration to the tumor site is a well-accepted contributor limiting immune checkpoint inhibitor efficacy. In this study, we combined intratumoral injection of plasmid IL-12 with electrotransfer and anti-PD-1 in metastatic B16F10 melanoma tumor model to increase tumor-infiltrating lymphocytes and improve therapeutic efficacy. We showed that effective anti-tumor responses required a subset of tumor-infiltrating CD8+ and CD4+ T cells. Additionally, the combination therapy induced higher MHC-I surface expression on tumor cells to hamper tumor cells escaping from immune recognition. Furthermore, we found that activating T cells by exposure to IL-12 resulted in tumors sensitized to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.
| S-EPMC9695203 | biostudies-literature
Project description:BackgroundHigh tumor-infiltrating lymphocytes (TILs) and hemorrhage are important prognostic factors in patients who have undergone craniotomy for melanoma brain metastases (MBM) before 2011 at the University of Pittsburgh Medical Center (UPMC). We have investigated the prognostic or predictive role of these histopathologic factors in a more contemporary craniotomy cohort from the University of North Carolina at Chapel Hill (UNC-CH). We have also sought to understand better how various immune cell subsets, angiogenic factors, and blood vessels may be associated with clinical and radiographic features in MBM.MethodsBrain tumors from the UPMC and UNC-CH patient cohorts were (re)analyzed by standard histopathology, tumor tissue imaging, and gene expression profiling. Variables were associated with overall survival (OS) and radiographic features.ResultsThe patient subgroup with high TILs in craniotomy specimens and subsequent treatment with immune checkpoint inhibitors (ICIs, n=7) trended to have longer OS compared to the subgroup with high TILs and no treatment with ICIs (n=11, p=0.059). Bleeding was significantly associated with tumor volume before craniotomy, high melanoma-specific expression of basic fibroblast growth factor (bFGF), and high density of CD31+αSMA- blood vessels. Brain tumors with high versus low peritumoral edema before craniotomy had low (17%) versus high (41%) incidence of brisk TILs. Melanoma-specific expression of the vascular endothelial growth factor (VEGF) was comparable to VEGF expression by TILs and was not associated with any particular prognostic, radiographic, or histopathologic features. A gene signature associated with gamma delta (gd) T cells was significantly higher in intracranial than same-patient extracranial metastases and primary melanoma. However, gdT cell density in MBM was not prognostic.ConclusionsICIs may provide greater clinical benefit in patients with brisk TILs in MBM. Intratumoral hemorrhage in brain metastases, a significant clinical problem, is not merely associated with tumor volume but also with underlying biology. bFGF may be an essential pathway to target. VEGF, a factor principally associated with peritumoral edema, is not only produced by melanoma cells but also by TILs. Therefore, suppressing low-grade peritumoral edema using corticosteroids may harm TIL function in 41% of cases. Ongoing clinical trials targeting VEGF in MBM may predict a lack of unfavorable impacts on TIL density and/or intratumoral hemorrhage.
| S-EPMC7860978 | biostudies-literature