Spatial analysis of the metastatic brain tumor immune and extracellular matrix microenvironment

Widodo, Samuel S; Dinevska, Marija; Cuzcano, Lucero; Papanicolaou, Michael; Cox, Thomas R.; Stylli, Stanley S.; Mantamadiotis, Theo

doi:10.1016/j.adcanc.2023.100096

Cited by 5 publications

(4 citation statements)

References 37 publications

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“…Several markers associated with different microglial and macrophage functions were investigated: HLA-DR is a Major Histocompatibility Class II cell-surface receptor responsible for antigen presentation for non-self-recognition, 47 and can mark proinflammatory brain TAMs; 48 Iba1 is a marker of microglial motility and migration; 49 P2RY12 is a purinergic receptor specifically expressed in homeostatic microglia; 50 , 51 CD68 is linked to phagocytosis as an endosomal/lysosomal-associated transmembrane glycoprotein; 52 , 53 and TREM2, which is associated with blood-derived infiltrative macrophages 54 , 55 and has recently been demonstrated to be expressed on a subset of anti-inflammatory TAMs in several cancer types. 28 , 56 CD163 and CD206 are more specific for perivascular macrophages in the brain and associated with an anti-inflammatory profile.…”

Section: Resultsmentioning

confidence: 99%

“… 28 , 56 CD163 and CD206 are more specific for perivascular macrophages in the brain and associated with an anti-inflammatory profile. 48 We studied the central effectors of IgG-mediated immune responses, FcγRs, by using markers for CD64 (FcgRI), a high-affinity-activating receptor for the Fc portion of IgG; CD32a (FcgRIIa) and CD16 (FcgRIII), which are low/medium-affinity-activating receptors of microglia/macrophages responding to immune complexes. 57 CD32a is considered to be a marker of phagocytic and anti-inflammatory microglia.…”

Section: Resultsmentioning

confidence: 99%

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Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins

Noorani,

Sidlauskas,

Pellow

et al. 2023

Brain Communications

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Glioblastoma is a devastating brain cancer for which effective treatments are required. Tumour-associated microglia and macrophages promote glioblastoma growth in an immune-suppressed microenvironment. Most recurrences occur at the invasive margin with surrounding brain, yet the relationships between microglia/macrophage phenotypes, T cells and Programmed death-ligand 1 (PD-L1, an immune checkpoint) across human glioblastoma regions are understudied. We performed quantitative immunohistochemical analysis of 15 markers of microglia/macrophage phenotypes (including anti-inflammatory markers TREM2 and CD163, and the low-affinity activating receptor CD32a), T cells, natural killer cells and PD-L1, in 59 human IDH1-wild-type glioblastoma multi-regional samples (n = 177; 1 sample at tumour core, 2 samples at the margins: the infiltrating zone and leading edge). Assessment was made for the prognostic value of markers; the results were validated in an independent cohort. Microglia/macrophage motility and activation (Iba1, CD68), PD-L1, and CD4+ T cells were reduced, and homeostatic microglia (P2RY12) were increased in the invasive margins compared to the tumour core. There were significant positive correlations between microglia/macrophage markers CD68 (phagocytic)/TREM2 (anti-inflammatory) and CD8+ T cells in the invasive margins but not in the tumour core (P<0.01). PD-L1 expression was associated with microglia/macrophage markers (including anti-inflammatory) CD68, CD163, CD32a and TREM2, only in the leading edge of glioblastomas (P<0.01). Similarly, there was a positive correlation between PD-L1 expression and CD8+ T cell infiltration in the leading edge (P<0.001). There was no relationship between CD64 (a receptor for autoreactive T cell responses) and CD8+/CD4+ T cells, or between the microglia/macrophage antigen presentation marker HLA-DR and microglial motility (Iba1) in the tumour margins. Natural killer cell infiltration (CD335+) correlated with CD8+ T cells, and with CD68/CD163/TREM2 anti-inflammatory microglia/macrophages at the leading edge. In an independent large glioblastoma cohort with transcriptomic data, positive correlations between anti-inflammatory microglia/macrophage markers (TREM2, CD163 and CD32a) and CD4+/CD8+/PD-L1 RNA expression were validated (P < 0.001). Finally, multivariate analysis showed high TREM2, PD-L1 and CD32a expression at the leading edge were significantly associated with poorer overall patient survival (hazard ratio = 2.05, 3.42 and 2.11 respectively), independent of clinical variables. In conclusion, anti-inflammatory microglia/macrophages, CD8+ T cells and PD-L1 are correlated in the invasive margins of glioblastoma, consistent with immune-suppressive interactions. High TREM2, PD-L1 and CD32a expression at the human glioblastoma leading edge are predictors of poorer overall survival. Given substantial interest in targeting microglia/macrophages together with immune checkpoint inhibitors in cancer, these data have major clinical implications.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins

Noorani,

Sidlauskas,

Pellow

et al. 2023

Brain Communications

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“…Even though this article does not cover the role of immune cells in BrMs, recent studies have demonstrated a complex interaction between tumor-associated ECM and tumor-infiltrating leukocytes, monocytes/macrophages, and granulocytes [ 108 ]. In the context of BrMs, collagen deposits were co-localized with CD3 + T cells and CD68 + macrophages [ 109 ], so it would be interesting to explore whether BrM-associated ECM may influence immune cell trafficking, antigen recognition, presentation, or cancer cell killing. In addition, this review predominantly covered biochemical cues derived from brain ECM in cancer metastasis; however, biophysical signals are also an important factor to regulate cancer cell dormancy and colonization.…”

Section: Discussion and Concluding Remarksmentioning

confidence: 99%

Critical functions of extracellular matrix in brain metastasis seeding

Yuzhalin,

2023

Cell. Mol. Life Sci.

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Human brain is characterized by extremely sparse extracellular matrix (ECM). Despite its low abundance, the significance of brain ECM in both physiological and pathological conditions should not be underestimated. Brain metastasis is a serious complication of cancer, and recent findings highlighted the contribution of ECM in brain metastasis development. In this review, we provide a comprehensive outlook on how ECM proteins promote brain metastasis seeding. In particular, we discuss (1) disruption of the blood–brain barrier in brain metastasis; (2) role of ECM in modulating brain metastasis dormancy; (3) regulation of brain metastasis seeding by ECM-activated integrin signaling; (4) functions of brain-specific ECM protein reelin in brain metastasis. Lastly, we consider the possibility of targeting ECM for brain metastasis management.

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“…In GBM, the collagen chaperone protein HSP47 overexpression has been shown to promote tumor formation through the TGF-ß mediated induction of ECM-related genes ( 50 ). While the proportion of collagen in GBM matches that of other cancers such as lung and breast, it differs in its decreased organization and more thin fibrillar collagen bundles ( 51 ). The characteristics of collagen in GBM seem to play an important role in tumorigenesis and immunosuppression, as GBM patients that had a more organized collagen structure showed higher survival and less tumor invasiveness than those with lesser organized collagen ( 52 ).…”

Section: The Role Of Ecm In Tumor Immunitymentioning

confidence: 99%

Understanding the glioblastoma tumor microenvironment: leveraging the extracellular matrix to increase immunotherapy efficacy

Collado,

Boland,

Ahrendsen

et al. 2024

Front. Immunol.

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Glioblastoma (GBM) accounts for approximately half of all malignant brain tumors, and it remains lethal with a five-year survival of less than 10%. Despite the immense advancements in the field, it has managed to evade even the most promising therapeutics: immunotherapies. The main reason is the highly spatiotemporally heterogeneous and immunosuppressive GBM tumor microenvironment (TME). Accounting for this complex interplay of TME-driven immunosuppression is key to developing effective therapeutics. This review will explore the immunomodulatory role of the extracellular matrix (ECM) by establishing its contribution to the TME as a key mediator of immune responses in GBM. This relationship will help us elucidate therapeutic targets that can be leveraged to develop and deliver more effective immunotherapies.

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Spatial analysis of the metastatic brain tumor immune and extracellular matrix microenvironment

Cited by 5 publications

References 37 publications

Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins

Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins

Critical functions of extracellular matrix in brain metastasis seeding

Understanding the glioblastoma tumor microenvironment: leveraging the extracellular matrix to increase immunotherapy efficacy

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