Unveiling the Inflammatory Landscape of Recurrent Glioblastoma through Histological-Based Assessments.

Simple Summary: Glioblastoma is a highly aggressive tumor, and despite standard-of-care therapy, tumor recurrence is inevitable. Recurrent glioblastoma (rGBM) remains a challenge to treat, given that it predominantly forms within a highly inflammatory tumor microenvironment (TME) that contributes to treatment resistance. However, the complex immune landscape of rGBM and how to effectively characterize it for therapeutic targeting remains poorly understood. To address this gap, this review exhaustively examines the existing body of literature on the immune characteristics of rGBM with a focus on the role of glioma-associated microglia and macrophages (GAMMs). We examine this inflammatory landscape through the lens of histological-based assessments given histological staining remains the gold standard of diagnostic identification of rGBM. We review canonical and emerging cell-specific markers of GAMMs and provide a guide of how these histological-based assessments can aid in characterizing the TME of rGBM and dissect how this landscape shifts in the context of treatment response. The glioblastoma (GBM) tumor microenvironment consists of a heterogeneous mixture of neoplastic and non-neoplastic cells, including immune cells. Tumor recurrence following standard-of-care therapy results in a rich landscape of inflammatory cells throughout the glioma-infiltrated cortex. Immune cells consisting of glioma-associated macrophages and microglia (GAMMs) overwhelmingly constitute the bulk of the recurrent glioblastoma (rGBM) microenvironment, in comparison to the highly cellular and proliferative tumor microenvironment characteristic of primary GBM. These immune cells dynamically interact within the tumor microenvironment and can contribute to disease progression and therapy resistance while also providing novel targets for emerging immunotherapies. Within these varying contexts, histological-based assessments of immune cells in rGBM, including immunohistochemistry (IHC) and immunofluorescence (IF), offer a critical way to visualize and examine the inflammatory landscape. Here, we exhaustively review the available body of literature on the inflammatory landscape in rGBM as identified through histological-based assessments. We highlight the heterogeneity of immune cells throughout the glioma-infiltrated cortex with a focus on microglia and macrophages, drawing insights from canonical and novel immune-cell histological markers to estimate cell phenotypes and function. Lastly, we discuss opportunities for immunomodulatory treatments aiming to harness the inflammatory landscape in rGBM. [ABSTRACT FROM AUTHOR]