TAMI-31. GLIOBLASTOMA GENETIC DRIVERS DICTATE THE FUNCTION OF TUMOR-ASSOCIATED MACROPHAGES/MICROGLIA AND RESPONSES TO CSF1R INHIBITION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi204-vi204
Author(s):  
Rohit Rao ◽  
Rong Han ◽  
Sean Ogurek ◽  
Lai Man Wu ◽  
Liguo Zhang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Tumor Therapy ◽  
Tumor Associated Macrophages ◽  
Transcriptomic Profiling ◽  
Angiogenic Therapy ◽  
Landscape Characterization ◽  
Specific Tumor ◽  
Glioma Growth ◽  
Human Gbm

Abstract Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment convey distinct sensitivities to TAM targeting. We generated syngeneic PDGFB-driven and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth and progression. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in tumor microenvironment compositions and functions between the proneural-like and mesenchymal-like glioma models. We found that the growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal human GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas mesenchymal RAS-driven gliomas elicited TAMs enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and tumor mass in RAS-driven gliomas. Our work identifies functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of microenvironment landscape characterization to optimally stratify glioma patients for TAM-targeted therapy.

Glioblastoma Genetic Drivers Dictate the Function of Tumor-Associated Macrophages/Microglia and Responses to CSF1R Inhibition

2021 ◽  
Author(s):  
Rohit Rao ◽  
Rong Han ◽  
Sean Ogurek ◽  
Chengbin Xue ◽  
Lai Man Wu ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Tumor Therapy ◽  
Pi3k Signaling ◽  
Tumor Associated Macrophages ◽  
Transcriptomic Profiling ◽  
Angiogenic Therapy ◽  
Specific Tumor ◽  
Glioma Growth

Abstract Background Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment convey distinct sensitivities to TAM targeting. Methods We generated syngeneic PDGFB-driven and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in tumor microenvironment cellular compositions and functions in PDGFB- and RAS-driven gliomas. Results We found that growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas TAMs in mesenchymal RAS-driven GBM were enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and changed the morphology of RAS-driven gliomas. Conclusions Our work identify functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of characterization of the microenvironment landscape in order to optimally stratify patients for TAM-targeted therapy.

scholarly journals Differential Polarization of Tumor-Associated Macrophages/Microglia Drives the Aggressiveness of Gliomas

2021 ◽  
Author(s):  
Nai-Wei Yao ◽  
Hsiu-Ting Lin ◽  
Ya-Lin Lin ◽  
Khamushavalli Geeviman ◽  
Fang Liao ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Wistar Rats ◽  
Tumor Development ◽  
C6 Glioma ◽  
Sprague Dawley ◽  
Tumor Associated Macrophages ◽  
Sd Rats ◽  
Glioma Growth

Abstract Background: Glioblastoma is the most aggressive subtype of brain tumors. The major component of tumor microenvironment in glioblastoma is tumor-associated macrophages (TAMs), which are associated with enhanced malignancy of glioblastoma. The polarization of macrophages to the pro-inflammatory M1 or anti-inflammatory M2 subtypes governed by the context of tumor microenvironment may dictate the aggressiveness and outcome of glioblastoma. Given that the immune responses to tumors vary distinctively among individuals due to intrinsic, environmental and genetic factors and that TAMs display a high level of diversity and plasticity, we aimed to examine the effects of differential polarization of TAMs on the glioblastoma development by implanting C6 glioma into brains of Sprague–Dawley (SD) and Wistar rats; these two rats have different genetic background and host microenvironment during tumor development. Methods: Sprague–Dawley (SD) and Wistar rats were implanted with C6 glioma in the brain. The measurement of tumor volumes, tumor morphology and tumor growth in C6 glioma implanted brains were measured by multi-parametric magnetic resonance imaging (MRI). Immunofluorescence staining was performed to analyze tumor angiogenesis and M1 and M2 TAMs in C6 gliomas. Results: By multi-parametric MRI measurement, C6 gliomas developed in the SD rats were characterized with enlarged tumors, accompanied with shorter animal survival. In comparison to the gliomas in Wistar rats, the accelerated tumor growth in SD rats was associated with greater extent of angiogenesis accompanied with higher levels of VEGF/VEGFR2. In support, C6 gliomas in SD rats were filtrated with TAMs characterized with a higher M2/M1 ratio, in contrast to the TAMs of a high M1/M2 ratio in Wistar rats. Attempts were made to shift the M2/M1 balance. Administration of the cytokine IFN-γ that induces M1 TAMs to SD rats greatly suppressed glioma formation, accompanied with a remarkable increase of M1 TAMs. Administration of the cytokines IL-4 plus IL-10 that induces M2 TAMs significantly promoted glioma growth in the Wistar rats, associated with an increase in the M2 TAMs. Conclusions: These results demonstrate an important role of TAMs in glioma pathogenesis and the crucial role of microenvironment in dictating the polarization of TAMs, suggesting that targeting or repolarization of TAMs may serve as an effective intervention for gliomas.

KS01.6.A Comparative analysis of the immune compartment in human glioblastoma and IDH-mutant WHO grade 4 astrocytoma reveals profound differences in microglia phenotypes

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii4-ii4
Author(s):  
R Sankowski ◽  
M Friedrich ◽  
L Bunse ◽  
H H Heiland ◽  
M Platten ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Rna Sequencing ◽  
Therapeutic Options ◽  
High Dimensional ◽  
Normal Brain ◽  
Who Grade ◽  
Idh Mutations ◽  
Single Cell Rna Sequencing ◽  
Human Gbm

Abstract BACKGROUND Glioblastoma (GBM) are the most common primary brain tumors. If untreated the average survival is around 12–18 months. Unfortunately, despite extensive research efforts, the therapeutic options remain limited. One major aspect complicating therapeutic development is an immunosuppressive tumor microenvironment. Isocitrate dehydrogenase (IDH)-mutant, WHO grade 4 astrocytomas appear histologically indistinguishable from GBM, but show significantly longer survival times. IDH mutations lead to changes in the tumor microenvironment with accrual of the neometabolite R-2-hydroxyglutarate. Previous studies on bulk transcriptomes have shown differences in the immune compartment of both tumor entities that were linked to the differences in clinical behavior. MATERIAL AND METHODS We have conducted high-dimensional comparative analyses of the myeloid compartment in surgically resected human GBM and IDH-mutant WHO grade 4 astrocytomas using single-cell RNA-Sequencing and immunohistochemistry. Histologically normal brain regions from epilepsy patients were used as controls. For analysis, whole-cell suspensions were prepared from freshly resected tumors or controls. Fluorescence activated cell sorting was used for myeloid cell enrichment. Samples were processed using the high-sensitivity single-cell RNA sequencing protocol CEL-Seq2. Seurat and StemID2 algorithms were used for clustering, differential gene expression and pseudotime analysis. Protein validation was achieved using immunohistochemistry. RESULTS We identified profound transcriptional changes of glioma-associated microglia in GBM with respect to control brain samples. Namely, we observed a global upregulation of major histocompatibility complex associated genes in GBM across all clusters. Additionally, we identified distinct myeloid subsets with phagocytic, hypoxia-associated and chemotactic transcriptomic signatures. Pseudotime analysis finely resolved transitional cell states. These changes were dramatically attenuated in IDH-mutant WHO grade 4 astrocytomas. The myeloid cells in these tumors resembled homeostatic microglia and showed an increased expression of cytokine and chemokine genes. CONCLUSION Here, we present a high-dimensional transcriptomic atlas of the myeloid compartment in human GBM and IDH-mutant WHO grade 4 astrocytomas. The identified differences point towards targeted therapeutic options via the modulation of the tumor microenvironment.

scholarly journals Mapping of single-cell landscape of acral melanoma and analysis of molecular regulatory network of tumor microenvironment

2021 ◽  
Author(s):  
Zan He ◽  
Zijuan Xin ◽  
Xiangdong Fang ◽  
Hua Zhao
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Interaction Network ◽  
Cell Types ◽  
Cell Interaction ◽  
Malignant Cells ◽  
Acral Melanoma ◽  
Asian Populations ◽  
Specific Tumor ◽  
Cell Transcriptome

Melanoma is a type of skin malignant tumor with high invasiveness, high metastasis, and poor prognosis. The incidence of melanoma continues to increase. Among them, the subtype of acral melanoma (AM) is more common in Asian populations. AM has higher degree, low immunotherapy response rate. With the help of single-cell sequencing technology provides new technical means for tumor microenvironment research, so that we can more easily explore specific tumor types suitable immunotherapy targets. However, no complete single-cell level differentiation map exists for the AM tumor microenvironment (TME). In this study, we used AM related sample and used the 10x Genomics single-cell transcriptome platform to draw a specific single-cell map of AM, understand the cell composition of AM, and analyze the interaction and molecular regulation of AM TME. Nine cell types were identified, of which malignant cells accounted for the largest proportion, followed by fibroblasts. And the cell interaction network shows that malignant cells, macrophages, B cells, T cells and fibroblasts play important roles in AM TME. Our research provides systematic theoretical guidance for the diagnosis and treatment of acral melanoma.

scholarly journals Sequential fate-switches in stem-like cells drive the tumorigenic trajectory from human neural stem cells to malignant glioma

Cell Research ◽  
2021 ◽  
Author(s):  
Xiaofei Wang ◽  
Ran Zhou ◽  
Yanzhen Xiong ◽  
Lingling Zhou ◽  
Xiang Yan ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Single Cell ◽  
De Novo ◽  
Early Stage ◽  
Lineage Tracing ◽  
Human Neural Stem Cells ◽  
Transcriptional Reprogramming ◽  
Neural Stem Progenitor Cells ◽  
Human Gbm ◽  
End Stage

AbstractGlioblastoma (GBM) is an incurable and highly heterogeneous brain tumor, originating from human neural stem/progenitor cells (hNSCs/hNPCs) years ahead of diagnosis. Despite extensive efforts to characterize hNSCs and end-stage GBM at bulk and single-cell levels, the de novo gliomagenic path from hNSCs is largely unknown due to technical difficulties in early-stage sampling and preclinical modeling. Here, we established two highly penetrant hNSC-derived malignant glioma models, which resemble the histopathology and transcriptional heterogeneity of human GBM. Integrating time-series analyses of whole-exome sequencing, bulk and single-cell RNA-seq, we reconstructed gliomagenic trajectories, and identified a persistent NSC-like population at all stages of tumorigenesis. Through trajectory analyses and lineage tracing, we showed that tumor progression is primarily driven by multi-step transcriptional reprogramming and fate-switches in the NSC-like cells, which sequentially generate malignant heterogeneity and induce tumor phenotype transitions. We further uncovered stage-specific oncogenic cascades, and among the candidate genes we functionally validated C1QL1 as a new glioma-promoting factor. Importantly, the neurogenic-to-gliogenic switch in NSC-like cells marks an early stage characterized by a burst of oncogenic alterations, during which transient AP-1 inhibition is sufficient to inhibit gliomagenesis. Together, our results reveal previously undercharacterized molecular dynamics and fate choices driving de novo gliomagenesis from hNSCs, and provide a blueprint for potential early-stage treatment/diagnosis for GBM.

scholarly journals Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer

2021 ◽  
Vol 9 (1) ◽  
pp. e001341
Author(s):  
Chunxiao Li ◽  
Xiaofei Xu ◽  
Shuhua Wei ◽  
Ping Jiang ◽  
Lixiang Xue ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
Tumor Immunotherapy ◽  
Therapeutic Strategies ◽  
Preclinical Studies ◽  
Future Prospects ◽  
Tumor Associated Macrophages

Macrophages are the most important phagocytes in vivo. However, the tumor microenvironment can affect the function and polarization of macrophages and form tumor-associated macrophages (TAMs). Usually, the abundance of TAMs in tumors is closely associated with poor prognosis. Preclinical studies have identified important pathways regulating the infiltration and polarization of TAMs during tumor progression. Furthermore, potential therapeutic strategies targeting TAMs in tumors have been studied, including inhibition of macrophage recruitment to tumors, functional repolarization of TAMs toward an antitumor phenotype, and other therapeutic strategies that elicit macrophage-mediated extracellular phagocytosis and intracellular destruction of cancer cells. Therefore, with the increasing impact of tumor immunotherapy, new antitumor strategies to target TAMs are now being discussed.

Photoactive conjugated polymer/graphdiyne nanocatalyst for CO2 reduce into CO in living cells for hypoxia tumor treatment

2021 ◽  
Author(s):  
Endong Zhang ◽  
Zicheng Zuo ◽  
Wen Yu ◽  
Hao Zhao ◽  
Shengpeng Xia ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Photodynamic Therapy ◽  
Tumor Microenvironment ◽  
Conjugated Polymer ◽  
Tumor Therapy ◽  
Living Cells ◽  
Tumor Treatment ◽  
Treatment Efficiency ◽  
Therapy Strategy ◽  
Co Gas

Carbon monoxide (CO) gas therapy has grown to be an emerging tumor therapy strategy to avoid low treatment efficiency of photodynamic therapy (PDT) caused by the hypoxia tumor microenvironment. However,...

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