Cellular and molecular features related to exceptional therapy response and extreme long‐term survival in glioblastoma

Abstract

Glioblastoma Multiforme (GBM) remains the most common malignant primary brain tumor with a dismal prognosis that rarely exceeds beyond 2 years despite extensive therapy, which consists of maximal safe surgical resection, radiotherapy, and/or chemotherapy. Recently, it has become clear that GBM is not one homogeneous entity and that both intra-and intertumoral heterogeneity contributes significantly to differences in tumoral behavior which may consequently be responsible for differences in survival. Strikingly and in spite of its dismal prognosis, small fractions of GBM patients seem to display extremely long survival, defined as surviving over 10 years after diagnosis, compared to the large majority of patients. Although the underlying mechanisms for this peculiarity remain largely unknown, emerging data suggest that still poorly characterized both cellular and molecular factors of the tumor microenvironment and their interplay probably play an important role. We hereby give an extensive overview of what is yet known about these cellular and molecular features shaping extreme long survival in GBM.

Single-cell profiling and zebrafish avatars revealLGALS1as immunomodulating target in glioblastoma

“…With a survival of 71 months (and still counting) this is 4.7 times longer than the median survival of a GBM patient receiving SoC treatment (i.e. 15 months) (Grochans et al, 2022), and this patient can be considered a "long-term survivor" (Decraene et al, 2023). This suggests that this patient is not only an outlier at the molecular level, as our models have demonstrated, but also in a clinical context.…”

“…Given the substantial heterogeneity and the consistent failure of current therapies in GBM, it is important to explore and develop more individualized GBM treatment strategies. Even though most clinical studies for GBM treatment have failed, there are often exceptional responders who benefit from a particular therapy (Decraene et al, 2023). The development and clinical validation of new preclinical models based on patient-derived samples that allow for a more precise reproduction of the patient's tumor complexity will facilitate a more accurate assessment of whether patients will respond to a specific treatment.…”

Standardizing analysis of intra‐tumoral heterogeneity with computational pathology

“…The implications of the tumor microenvironment on glioblastoma progression also extend to immune cell interactions, which have been established to play a significant role on phenotype and prognosis. Tumor associated macrophages, specifically monocytes, make up the largest non‐neoplastic cell population in the glioblastoma tumor microenvironment, making their activity a natural point of interest 45 . They are known to promote tumor growth by suppressing effector T‐cell function, and stimulating tumor proliferation through secretion of pro‐angiogenic and pro‐mitogenic factors, such as transforming growth factor‐beta (TGF‐β) 45,46 .…”

“…Tumor associated macrophages, specifically monocytes, make up the largest non‐neoplastic cell population in the glioblastoma tumor microenvironment, making their activity a natural point of interest 45 . They are known to promote tumor growth by suppressing effector T‐cell function, and stimulating tumor proliferation through secretion of pro‐angiogenic and pro‐mitogenic factors, such as transforming growth factor‐beta (TGF‐β) 45,46 . Interestingly, a recent study found that macrophages have a causal role in inducing the MES‐like state transition in glioblastoma cells 47 .…”

“…45 They are known to promote tumor growth by suppressing effector T-cell function, and stimulating tumor proliferation through secretion of pro-angiogenic and pro-mitogenic factors, such as transforming growth factor-beta (TGF-β). 45,46 Interestingly, a recent study found that macrophages have a causal role in inducing the MES-like state transition in glioblastoma cells. 47 To highlight this, the team used single-cell data, in vitro mouse models, and gliomaspheres to reveal ligand-receptor interactions via macrophage secretion of macrophagederived oncostatin M (OSM), its receptor (OSMR), and subsequent STAT3 signaling in glioblastoma cells to induce mesenchymal transition.…”