Tumor-Associated Macrophages and Adrenomedullin Targeting to Enhance Glioblastoma Treatment Outcomes

Glioma is the most prevalent malignant tumor affecting the central nervous system, and glioblastoma (GBM) is its most aggressive and fatal form.1–3 Despite recent advances in therapy, GBM remains challenging to treat, with a median survival of only 14-17 months and a five-year survival rate of approximately 5 %.1,2

A significant factor contributing to these grim statistics is the heterogeneity of tumor cells and their interactions with the tumor microenvironment (TME).3 The TME plays a key role in determining tumor behavior, progression and metastasis, and can also induce resistance to therapeutic agents like chemotherapy and immunotherapy.2,3 In glioblastoma, the TME is highly immunosuppressive,2,3 which has recently been shown to be generated by a symbiotic interaction between the TME and the glioma cells themselves.3 Therefore, targeting this interaction has become a potential strategy to improve the efficacy of anti-tumor therapies in GBM.3

Among TME components, tumor-associated macrophages (TAMs) are the most common immune cells, constituting up to 50 % of the tumor mass in GBM.2,3 TAMs play a critical role in promoting tumor angiogenesis, immune evasion and tumor proliferation,2 but attempts to target them have not been successful in clinical trials, likely due to our limited knowledge and characterization of these cells and their behavior.3,4 Recent advances in single-cell technologies have opened the door to a more in-depth understanding, which could pave the way to new, more effective therapeutic options.1,3,4

Image Credit: Lightspring/Shutterstock.com

Single-cell advances

In a recent study, researchers from the Institute of Pathology and Southwest Cancer Center in Chongqing, China, used single-cell and spatial transcriptomics to characterize subsets of TAMs known as monocyte-derived TAMs (Mo-TAMs).4 The team studied samples from 51 patients with glioblastoma or glioma.4

The team first identified six discrete clusters of Mo-TAMs by functional and spatial characteristics. They decided to focus on one of these clusters that was strongly associated with hypoxia (referred to as Hypoxia-TAM) due to the role of hypoxia as a hallmark of tumors in processes like neovascularization, inflammation, and treatment resistance. The team explored how hypoxia impacts Hypoxia-TAM and how Hypoxia-TAM interacts with other cells to further tumor progression.4

Uncovering instability

The team discovered that Hypoxia-TAM was spatially associated with destabilized microvessels in the peri-necrotic regions of GBMs. They showed that Hypoxia-TAM oversecrete adrenomedullin (ADM) which destabilizes endothelial adherens junctions, promoting a hyperpermeable tumor vasculature.4

To explore the impact on tumor development and treatment, the researchers used a knockout mouse model to study how human GBM xenografts were impacted by the absence of ADM. This demonstrated a restoration of the VE-cadherin – a marker for endothelial junction adhesion – and improved vascular integrity with reduced vascular leakage in the xenografts.4 Similarly, the use of an ADM antagonist (AMA) in a xenograft model of GBM led to the restoration of VE-cadherin expression, the preservation of endothelial junctions, and a decrease in tumor vascular permeability.4

The team then investigated whether AMA could be combined with anti-tumor agents to improve their efficacy. Dabrafenib is used to treat brain tumors with specific genetic mutations but is usually only able to achieve low intratumoral concentrations, partly due to the hyperpermeable vasculature of brain tumors. In a xenograft model, the team co-administered dabrafenib and AMA and compared the results with those of the control or agent alone. They found that the combination provided synergistic therapeutic effects, reducing tumor burden and leading to a corresponding improvement in survival.4

Advancing therapeutic applications

Writing in Cancer Cell, the team says that their findings could lead to strategies to normalize tumor vasculature, particularly by targeting ADM, which they have identified as an “orchestrator” of destabilized endothelial connections. They suggest that in the future, therapies that block ADM could be used as an alternative to focused ultrasound therapy, which is associated with a risk of serious adverse effects. The blockade of ADM could not only enhance the perfusion of anti-tumor drugs in GBM but could also have a role in improving the efficacy of immunotherapy. What’s more, since destabilized vasculature and tumor perfusion are common across brain tumors, the team states that the results could have implications that extend beyond GBM.4

TissueGnostics innovation

These findings were made possible through the use of the TisseFAXS Quantitative Imaging System and TissueGnostics StrataQuest analysis software. TissueFAXS provides researchers with a versatile tool for whole-slide multispectral imaging and analysis. It is capable of automated scanning of up to 120 standard-size slides and can scan up to 8 markers in one run, making it ideal for studying the spatial association of markers, as in this study.

The team combined this with TissueGnostics’ most powerful image-processing software, StrataQuest, to provide automated context-based quantitative analysis and took advantage of its ability to remove nonspecific background and optimize vascular and marker identification. StrataQuest now comes equipped with over 50 apps to perform automated analysis, but advanced users can also develop their own solutions, making this a highly adaptable, powerful tool for a diverse range of imaging purposes.

References

  1. Batchu S, Hanafy KA, Redjal N, et al. Single-cell analysis reveals diversity of tumor-associated macrophages and their interactions with T lymphocytes in glioblastoma. Sci Rep. 2023;13(1):20874. doi: 10.1038/s41598-023-48116-2.
  2. Tang F, Wang Y, Zeng Y, et al. Tumor-associated macrophage-related strategies for glioma immunotherapy. NPJ Precis Oncol. 2023;7(1):78. doi: 10.1038/s41698-023-00431-7.
  3. Khan F, Pang L, Dunterman M, L et al. Macrophages and microglia in glioblastoma: heterogeneity, plasticity, and therapy. J Clin Invest. 2023;133(1):e163446. doi: 10.1172/JCI163446.
  4. Wang W, Li T, Cheng Y, et al. Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalization. Cancer Cell. 2024;42(5):815-832.e12.

About TissueGnostics

TissueGnostics (TG) is an Austrian company focusing on integrated solutions for high content and/or high throughput scanning and analysis of biomedical, veterinary, natural sciences, and technical microscopy samples.

TG has been founded by scientists from the Vienna University Hospital (AKH) in 2003. It is now a globally active company with subsidiaries in the EU, the USA, and China, and customers in 30 countries.

TissueGnostics portfolio

TG scanning systems are currently based on versatile automated microscopy systems with or without image analysis capabilities. We strive to provide cutting-edge technology solutions, such as multispectral imaging and context-based image analysis as well as established features like Z-Stacking and Extended Focus. This is combined with a strong emphasis on automation, ease of use of all solutions, and the production of publication-ready data.

The TG systems offer integrated workflows, i.e. scan and analysis, for digital slides or images of tissue sections, Tissue Microarrays (TMA), cell culture monolayers, smears, and other samples on slides and oversized slides, in Microtiter plates, Petri dishes and specialized sample containers. TG also provides dedicated workflows for FISH, CISH, and other dot structures.

TG analysis software apart from being integrated into full systems is fully standalone capable and supports a wide variety of scanner image formats as well as digital images taken with any microscope.

TG also provides routine hematology scanning and analysis systems for peripheral blood, bone marrow, and body fluids.


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Last updated: Jun 19, 2024 at 1:07 PM

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