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Trends in Pharmacological Sciences
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Pharmacological targeting of the tumor–immune symbiosis in glioblastoma

  • Lizhi Pang
    Affiliations
    Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
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  • Author Footnotes
    2 These authors contributed equally to this work
    Fatima Khan
    Footnotes
    2 These authors contributed equally to this work
    Affiliations
    Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Search for articles by this author
  • Author Footnotes
    2 These authors contributed equally to this work
    Madeline Dunterman
    Footnotes
    2 These authors contributed equally to this work
    Affiliations
    Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Search for articles by this author
  • Peiwen Chen
    Correspondence
    Correspondence:
    Affiliations
    Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
    Search for articles by this author
  • Author Footnotes
    2 These authors contributed equally to this work

      Highlights

      • Myeloid cells, such as glioma-associated macrophages and microglia (GAMs) and myeloid-derived suppressor cells (MDSCs), are highly infiltrated into the glioblastoma (GBM) tumor microenvironment (TME) and exhibit symbiotic interactions with GBM cells and other components (e.g., T cells) of the TME. Such symbiosis not only promotes tumor growth but also induces an immunosuppressive TME in GBM.
      • Pharmacological blockade of the tumor–immune symbiosis (e.g., the GBM-GAM, GBM–MDSC, and GBM-T cell symbiosis) inhibits tumor progression by modulating the biology of both GBM cells and immune cells.
      • Immunotherapies, such as immune checkpoint inhibitor (ICI) therapies, offer limited clinical benefits in GBM patients. Pharmacological targeting of the tumor-myeloid cell symbiosis increases the infiltration and activation of T cells and synergizes with ICI therapies in GBM.
      Glioblastoma (GBM) is the most common and highly lethal form of primary brain tumor in adults. The median survival of GBM patients is approximately 14–16 months despite multimodal therapies. Emerging evidence has substantiated the critical role of symbiotic interactions between GBM cells and noncancerous immune cells (e.g., myeloid cells and T cells) in regulating tumor progression and therapy resistance. Approaches to target the tumor–immune symbiosis have emerged as a promising therapeutic strategy for GBM. Here, we review the recent developments for pharmacological targeting of the GBM-immune symbiosis and highlight the role of such strategies to improve the effectiveness of immunotherapies in GBM.

      Keywords

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      Glossary

      Aptamer
      short single-stranded DNA or RNA molecules that can selectively bind to distinct targets (e.g., peptides, proteins, carbohydrates, toxins, and small molecules).
      Blood–brain barrier (BBB)
      a system of brain microvascular endothelial cells that can protect the brain from toxic substances in the blood, supply brain tissues with nutrients, and filter harmful compounds from brain back into the blood stream.
      Circadian locomotor output cycles kaput (CLOCK)-BMAL1 complex
      a heterodimeric transcriptional activator that coordinates rhythmic gene expression and controls biological functions of the circadian clock.
      Glioma-associated macrophages and microglia (GAMs)
      infiltrating bone marrow-derived macrophages and brain-resident microglia in the GBM TME that originate from the bone marrow and progenitors seeding the embryonic yolk, respectively.
      Glioma stem cells (GSCs)
      a small population of cells within GBM tumors that have self-renewal and tumorigenic ability and can induce tumor recurrence and treatment resistance.
      Immune checkpoint inhibitor (ICI)
      a class of agents that trigger antitumor immune response by targeting immune checkpoint molecules.
      Mass cytometry (CyTOF)
      a variation of flow cytometry that allows the quantification of multiple labeled targets (up to 50) simultaneously on the surface and interior of single cells.
      Myeloid cells
      a group of immune cells (e.g., macrophages, MDSCs, neutrophils, monocytes, dendritic cells, and mast cells) that originate from hematopoietic stem cells in the bone marrow.
      Myeloid-derived suppressor cells (MDSCs)
      a population of immature myeloid cells (including polymorphonuclear and monocytic MDSCs) that can suppress antitumor immunity and promote tumor progression.
      Organoids
      3D multicellular in vitro tissue constructs that can mimic the in vivo TME.
      Patient-derived xenografts (PDX)
      cancer patient-derived xenograft mouse models that can reflect the properties of original patient tumors.
      Single-cell RNA sequencing (scRNA-seq)
      an optimized next-generation sequencing (NGS) strategy that provides the gene expression profiles at a single-cell level.
      Symbiotic interaction
      a type of interaction between cells (e.g., GBM cells and myeloid cells) in which at least one cell type benefits.
      T cell exhaustion
      a state of T cell dysfunction in cancer that is characterized by poor effector function and enhanced expression of inhibitory immune checkpoint molecules/receptors.
      T cell tolerance
      a state of unresponsiveness of T cells toward specific self or non-self-antigens, which negatively affects an individual’s immune system.
      Th1-like CD4 T cells
      a subset of CD4 T cells that can secrete inflammation-related cytokines (e.g., IFNγ and TNFα) and exhibit an antitumor immune response.
      Treg cells
      a specialized population of helper T cells that suppress antitumor immunity.
      Tumor microenvironment (TME)
      stromal components (e.g., blood vessels, immune cells, fibroblasts, signaling molecules, and extracellular matrix) of a tumor that support tumor progression.
      Tumor-on-a-chip
      a microfluidic device that can maintain the structural and functional units of tumor cells in vitro.
      Whole-exome sequencing
      a technology that can sequence all protein-coding regions of the genome.