Tumor associated microglia/macrophages utilize GPNMB to promote tumor growth and alter immune cell infiltration in glioma

Yalcin, Fatih; Haneke, Hannah; Efe, Ibrahim E.; Kuhrt, Leonard D.; Motta, Edyta; Nickl, Bernadette; Flüh, Charlotte; Synowitz, Michael; Dzaye, Omar; Bader, Michael; Kettenmann, Helmut

doi:10.1186/s40478-024-01754-7

Cited by 4 publications

(1 citation statement)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The extracellular domain of GPNMB is found binding to several receptors on tumour cells. And its intracellular domain benefits to macrophage activity through autocrine effects [ 75 ]. With the expression of GPNMB in macrophages, there were a few studies that described the increased production of anti-inflammatory cytokines and the inhibition of T-cell responses [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

Multiomics integration-based immunological characterizations of adamantinomatous craniopharyngioma in relation to keratinization

Xu,

Wu,

et al. 2024

Cell Death Dis

View full text Add to dashboard Cite

Although adamantinomatous craniopharyngioma (ACP) is a tumour with low histological malignancy, there are very few therapeutic options other than surgery. ACP has high histological complexity, and the unique features of the immunological microenvironment within ACP remain elusive. Further elucidation of the tumour microenvironment is particularly important to expand our knowledge of potential therapeutic targets. Here, we performed integrative analysis of 58,081 nuclei through single-nucleus RNA sequencing and spatial transcriptomics on ACP specimens to characterize the features and intercellular network within the microenvironment. The ACP environment is highly immunosuppressive with low levels of T-cell infiltration/cytotoxicity. Moreover, tumour-associated macrophages (TAMs), which originate from distinct sources, highly infiltrate the microenvironment. Using spatial transcriptomic data, we observed one kind of non-microglial derived TAM that highly expressed GPNMB close to the terminally differentiated epithelial cell characterized by RHCG, and this colocalization was verified by asmFISH. We also found the positive correlation of infiltration between these two cell types in datasets with larger cohort. According to intercellular communication analysis, we report a regulatory network that could facilitate the keratinization of RHCG+ epithelial cells, eventually causing tumour progression. Our findings provide a comprehensive analysis of the ACP immune microenvironment and reveal a potential therapeutic strategy base on interfering with these two types of cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Multiomics integration-based immunological characterizations of adamantinomatous craniopharyngioma in relation to keratinization

Xu,

Wu,

et al. 2024

Cell Death Dis

View full text Add to dashboard Cite

show abstract

Targeting of TAMs: can we be more clever than cancer cells?

Kzhyshkowska,

Shen,

Larionova

2024

Cell Mol Immunol

View full text Add to dashboard Cite

АbstractWith increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. Our review summarizes the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. We present the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. Our review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, we explain how TAMs interfere with currently used anticancer therapeutics and summarize the most advanced data from clinical trials, which we divide into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages.

show abstract

ASO-mediated knockdown of GPNMB in mutant-GRNandGrn-deficient peripheral myeloid cells disrupts lysosomal function and immune responses

Wallings,

Gillett,

Staley

et al. 2024

Preprint

View full text Add to dashboard Cite

Background: Increases in GPNMB are detectable in FTD-GRN cerebrospinal fluid (CSF) and post-mortem brain, and brains of aged Grn-deficient mice. Although no upregulation of GPNMB is observed in the brains of young Grn-deficient mice, peripheral immune cells of these mice do exhibit this increase in GPNMB. Importantly, the functional significance of GPNMB upregulation in progranulin-deficient states is currently unknown. Given that GPNMB has been discussed as a potential therapeutic target in GRN-mediated neurodegeneration, it is vital for the field to determine what the normal function of GPNMB is in the immune system, and whether targeting GPNMB will elicit beneficial or deleterious effects. Methods: The effects of GPNMB knock-down via antisense oligonucleotide (ASO) were assessed in peripheral blood mononuclear cells (PBMCs) from 25 neurologically healthy controls (NHCs) and age- and sex-matched FTD-GRN patients, as well as peritoneal macrophages (pMacs) from progranulin-deficient (Grn-/-) and B6 mice. Lysosomal function, antigen presentation and MHC-II processing and recycling were assessed, as well as cytokine release and transcription. Results: We demonstrate here that ASO-mediated knockdown of GPNMB increases lysosomal burden and cytokine secretion in FTD-GRN carrier and neurologically healthy controls (NHCs) monocytes. ASO-mediated knockdown of GPNMB in Grn-deficient macrophages decreased lysosomal pan-cathepsin activity and protein degradation.. In addition, ASO-mediated knockdown of GPNMB increased MHC-II surface expression, which was driven by decreased MHC-II uptake and recycling, in macrophages from Grn-deficient females. Finally, ASO-mediated knockdown of GPNMB dysregulated IFNy-stimulated cytokine transcription and secretion by mouse macrophages due to the absence of regulatory actions of the GPNMB extracellular fragment (ECF). Conclusions: Our data herein reveals that GPNMB has a regulatory effect on multiple immune effector functions, including capping inflammation and immune responses in myeloid cells via secretion of its ECF. Therefore, in progranulin-deficient states, the drastic upregulation in GPNMB transcript and protein may represent a compensatory mechanism to preserve lysosomal function in myeloid cells. These novel findings indicate that targeted depletion in FTD-GRN would not be a rational therapeutic strategy because it is likely to dysregulate important immune cell effector functions.

show abstract

Tumor associated microglia/macrophages utilize GPNMB to promote tumor growth and alter immune cell infiltration in glioma

Cited by 4 publications

References 49 publications

Multiomics integration-based immunological characterizations of adamantinomatous craniopharyngioma in relation to keratinization

Multiomics integration-based immunological characterizations of adamantinomatous craniopharyngioma in relation to keratinization

Targeting of TAMs: can we be more clever than cancer cells?

ASO-mediated knockdown of GPNMB in mutant-GRNandGrn-deficient peripheral myeloid cells disrupts lysosomal function and immune responses

Contact Info

Product

Resources

About