Immune Microenvironment in Glioblastoma Subtypes

Abstract

Glioblastomas (GBMs) are the most common and aggressive primary brain tumors. Due to their malignant growth and invasion into the brain parenchyma coupled with resistance to therapy, GBMs are among the deadliest of all cancers. GBMs are highly heterogeneous at both the molecular and histological levels. Hallmark histological structures include pseudopalisading necrosis and microvascular proliferation. In addition to high levels of intratumoral heterogeneity, GBMs also exhibit high levels of inter-tumoral heterogeneity. The major non-neoplastic cell population in the GBM microenvironment includes cells of the innate immune system called tumor-associated macrophages (TAMs). Correlative data from the literature suggest that molecularly distinct GBM subtypes exhibit differences in their microenvironment. Data from mouse models of GBM suggest that genetic driver mutations can create unique microenvironments. Here, we review the origin, features, and functions of TAMs in distinct GBM subtypes. We also discuss their interactions with other immune cell constituents and discuss prospects of therapeutically targeting TAMs to increase the efficacy of T-cell functions.

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

“…The mechanisms underlying interpatient heterogeneity of immune response in GBM are unclear . β‐catenin‐mediated immune evasion pathways operate in CIC4, the group with the poorest prognosis in melanoma , whereas in this study we found no evidence of CTNNB1 differential expression between CIC2 and CIC4, nor was their mutational burden significantly different.…”

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

“…The mechanisms underlying inter-patient heterogeneity of immune response in GBM are unclear (45). b-catenin mediated immune evasion pathways operate in CIC4, the group with the poorest prognosis in melanoma (14), whereas here we found no evidence of CTNNB1 differential expression between CIC2 and 4 and neither was their mutational burden significantly different.…”

Deletion of the RNA regulator HuR in tumor‐associated microglia and macrophages stimulates anti‐tumor immunity and attenuates glioma growth

“…Scale bar,50 μm. M1-like TAMs, however, are cytotoxic to tumors, so the shift we observed likely contributed to the attenuated tumor growth and prolonged survival in HuR KO mice (Chen & Hambardzumyan, 2018;Mantovani, Marchesi, Malesci, Laghi, & Allavena, 2017). In fact, reprogramming TAMs to an M1-like phenotype represents a therapeutic approach being pursued in the development of treatments for GB (Roesch et al, 2018).…”

“…PD‐L1 is a transmembrane protein, expressed by tumor cells and TAMs that engages with PD‐1 receptors on T cells and inhibits their activation and anti‐tumor immunity (Sun et al, ). While the relative contribution of PD‐L1 (tumor cell versus TAM) as a source of immunosuppression varies among tumor types, TAMs can sustain PD‐L1 expression and provide extended immunosuppression (Chen & Hambardzumyan, ; Juneja et al, ; Noguchi et al, ). PD‐L1 is detected in the majority of human GB tumors, including TAMs, and correlates with tumor grade, markers of proliferation and angiogenesis, and worse prognosis (Wöhrer et al, ; Xue et al, ; Xue, Song, & Yu, ).…”

“…(tumor cell versus TAM) as a source of immunosuppression varies among tumor types, TAMs can sustain PD-L1 expression and provide extended immunosuppression (Chen & Hambardzumyan, 2018;Juneja et al, 2017;Noguchi et al, 2017). PD-L1 is detected in the majority of human GB tumors, including TAMs, and correlates with tumor grade, markers of proliferation and angiogenesis, and worse prognosis (Wöhrer et al, 2014;Xue, Song, & Yu, 2017).…”