Immune microenvironment of gliomas

Abstract

High-grade gliomas are rapidly progressing tumors of the central nervous system (CNS) with a very poor prognosis despite extensive resection combined with radiation and/or chemotherapy. Histopathological and flow cytometry analyses of human and rodent experimental gliomas revealed heterogeneity of a tumor and its niche, composed of reactive astrocytes, endothelial cells, and numerous immune cells. Infiltrating immune cells consist of CNS resident (microglia) and peripheral macrophages, granulocytes, myeloid-derived suppressor cells (MDSCs), and T lymphocytes. Intratumoral density of glioma-associated microglia/macrophages (GAMs) and MDSCs is the highest in malignant gliomas and inversely correlates with patient survival. Although GAMs have a few innate immune functions intact, their ability to be stimulated via TLRs, secrete cytokines, and upregulate co-stimulatory molecules is not sufficient to initiate antitumor immune responses. Moreover, tumor-reprogrammed GAMs release immunosuppressive cytokines and chemokines shaping antitumor responses. Both GAMs and MDSCs have ability to attract T regulatory lymphocytes to the tumor, but MDSCs inhibit cytotoxic responses mediated by natural killer cells, and block the activation of tumor-reactive CD4 T helper cells and cytotoxic CD8 T cells. The presence of regulatory T cells may further contribute to the lack of effective immune activation against malignant gliomas. We review the immunological aspects of glioma microenvironment, in particular composition and various roles of the immune cells infiltrating malignant human gliomas and experimental rodent gliomas. We describe tumor-derived signals and mechanisms driving myeloid cell accumulation and reprogramming. Although, understanding the complexity of cell-cell interactions in glioma microenvironment is far from being achieved, recent studies demonstrated several glioma-derived factors that trigger migration, accumulation, and reprogramming of immune cells. Identification of these factors may facilitate development of immunotherapy for gliomas as immunomodulatory and immune evasion mechanisms employed by malignant gliomas pose an appalling challenge to brain tumor immunotherapy.

High expression of COPB2 predicts adverse outcomes: A potential therapeutic target for glioma

“…Glioma cells could release multiple cytokines that promote the infiltration of various immune cells such as MDSCs, microglia, Tregs, macrophages, CD8 T cells, and CD4 T cells into the tumor microenvironment, as tumors not only recruit immune cells, but also transform said cells into phenotypes that can help tumor cells evade immune system surveillance (Table ). For example, Roesch et al reported that macrophages/glioma‐associated microglia (GAMs) tend to gather in tumor sites and generate an immunosuppressive tumor microenvironment which promote glioma invasion, growth, and angiogenesis . Interestingly, one novel discovery of the present study is that COPB2 was involved in the immune microenvironment of glioma.…”

“…Glioma cells could release multiple cytokines that promote the infiltration of various immune cells such as MDSCs, microglia, Tregs, macrophages, CD8 T cells, and CD4 T cells into the tumor microenvironment, 22 as tumors not only recruit immune cells, but also transform said cells into phenotypes that can help tumor cells evade immune system surveillance ( In recent years, the use of immune checkpoint inhibitors (ICIs) has been popular in the treatment of malignant tumors. 25,26 Some ICIs, such as anti-PD-1 antibody, are superior to traditional chemoradiotherapy in terms of its clinical curative effect.…”

Characterization of transcriptome profile and clinical features of a novel immunotherapy target CD204 in diffuse glioma

“…6 Unlike classically activated M1 macrophages, which are characterized by their promotion of an antitumor response, TAMs have an immunosuppressive role, thus being defined as the alternatively activated M2 phenotype. [7][8][9] TAMs promote glioma progression through secretion of TGFβ1, IL-6, VEGF, PDGF, periostin, MMP2, and MMP9, maintaining the phenotype of glioma stem-like cells, promoting angiogenesis, and regulating degradation of the extracellular matrix (ECM), thus leading to glioma growth, invasion, and the formation of distant pre-metastatic niches. 10,11 Moreover, the immunosuppressive microenvironment induced by TAMs suppresses the systemic immune response by blocking T-cell proliferation, increasing T-cell apoptosis, inhibiting cytotoxic T lymphocyte (CTL) response, and promoting other immunosuppressive cells such as MDSCs and Tregs.…”

The Role of Astrocytes in Tumor Growth and Progression

“…Only upon CNS injury do some of these cellular barriers become fenestrated to allow for immune cell entrance. Although microglia are thought to be the main regulator of immune responses within the brain, astrocytes (and other cells) also play key roles in this function [143]. A vast amount of work investigating the astrocyte function in either normal or activated state is often related to the regulation of the immune environment in the CNS, as shown in functional studies and astrocyte secretome studies, summarized well by Sofroniew et al [144][145][146][147].…”