Brain Tumor Microenvironment and Host State: Implications for Immunotherapy

Abstract

Glioblastoma (GBM) is a highly lethal brain tumor with poor responses to immunotherapies that have been successful in more immunogenic cancers with less immunosuppressive tumor microenvironments (TME). The GBM TME is uniquely challenging to treat due to tumor cellextrinsic components that are native to the brain, as well as tumor-intrinsic mechanisms that aid in immune evasion. Lowering the barrier of immunosuppression by targeting the genetically stable tumor stroma presents opportunities to treat the tumor in a way that circumvents the complications of targeting a constantly mutating tumor with tumor antigen-directed therapies. Tumor-associated monocytes, macrophages, and microglia are a stromal element of particular interest. Macrophages and monocytes compose the bulk of infiltrating immune cells and are considered to have protumor and immunosuppressive effects. Targeting these cells or other stromal elements is expected to convert what is considered the "cold" TME of GBM to a more "hot" TME phenotype. This conversion could increase the effectiveness of what have become conventional frontline immunotherapies in GBM-creating opportunities for better treatment through combination therapy.

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance

“…Moreover, profound immunosuppression occurs in the tumor microenvironment, particularly in the context of cell-mediated immunity [31], which is driven by an array of cytokines, such as prostaglandin E2, transforming growth factor beta (TGF-β), matrix metallopeptidase 9, IL-10, programmed death-ligand 1 (PD-L1), granulocyte colony stimulating factor, VEGF, and S100A4 [18,31,33,52,53]. At a mechanistic level, most proposed pathways to mediate immunosuppression in GBM are those involving signal transducer and activator of transcription 3 (STAT-3) [54,55], phosphoinositide 3 kinase, Ras-mitogen-activated protein kinase, wingless-related integration site/β-catenin, and indolamine 2, 3-dioxygenase [56].…”

Meningeal lymphatic vessels regulate brain tumor drainage and immunity

“…Brain tumors, including primary and metastatic tumors, are among the most feared of all forms of cancer with very limited treatment options and a poor prognosis. [17][18][19] Malignant cerebral gliomas, the most common primary tumor in the CNS, comprising 80% of all malignant primary brain tumors, 20 have a strong tendency to infiltrate. 21 Nevertheless, metastatic brain tumors are the most frequently occurring intracranial tumors.…”

Circulating biomarkers in patients with glioblastoma

“…However, GBM is thought to have a low mutational burden and to be immunologically cold. 21 Moreover, other studies have reported that immunotherapies can alter the tumour microenvironment in GBM, which may influence patients' response to treatment and culminate in benefits from combined therapies. 15,22 The diagnosis of GBM is currently based on imaging techniques and tissue biopsies.…”