Abstract
Glioblastoma (GBM) is among the most aggressive of brain tumors and confers a dismal prognosis despite advances in surgical technique, radiation delivery methods, chemotherapy, and tumor-treating fields. While immunotherapy (IT) has improved the care of several adult cancers with previously dismal prognoses, monotherapy with IT in GBM has shown minimal response in first recurrence. Recent discoveries in lymphatics and evaluation of blood brain barrier offer insight to improve the use of ITs and determine the best combinations of therapies, including radiation. We highlight important features of the tumor immune microenvironment in GBM and potential for combining radiation and immunotherapy to improve prognosis in this devastating disease.
Highlights
Glioblastoma (GBM), a high-grade glial tumor, is the most frequent malignant primary brain tumor in adults [1]
Whether these mechanisms are initiated in irradiated GBM remains unknown, but current data suggests that activation CGAS-stimulator of the interferon genes (STING) in myeloid cells is important for anti-tumor immunity against this tumor type [106, 107]
Ongoing clinical trials assessing the combination of IT with either standard fractionation or hypofractionation regimen in central nervous system (CNS) diseases (Table 1) may provide some indication on the optimal radiation regimen and sequencing of IT to generate GBM-targeted anti-tumor immune responses. Another major limitation to Radiation therapy (RT)-induced anti-tumor immunity is the activation of latent transforming growth factor-beta (TGFb) that stem for the tumor microenvironment (TME)
Summary
Glioblastoma (GBM), a high-grade glial tumor, is the most frequent malignant primary brain tumor in adults [1]. The description of the afferent mechanism for CNS engagement in regional lymphatic [22,23,24] together with the discovery of the glymphatic (gliallymphatic) system that links the parenchyma and the interstitium to the cerebrospinal fluid (CSF) spaces, started to challenge the concept of the brain as immunologically silenced Another breakthrough in the field of brain immunology was the identification of a functional meningeal lymphatic network that enables the drainage of immune cells, macromolecules and fluids from the CNS to the deep cervical lymph nodes (dcLN) [4, 25]. TAMs promote immunosuppression by the production of arginase, transforming growth factor-beta (TGFb), interleukin (IL)-10 and IL-6, among others which collectively inhibit both the innate and adaptive immune systems with suppression of NK activity and T cell activation and proliferation [52,53,54,55] Another mechanism responsible for immunosuppression and the lack of response of IT strategies in GBM patient is the low representation of T cells in the tumor. Studies have demonstrated that T cells influx in GBM is offset as a result of [1] reduced T cells production subsequent to thymic involution [56],
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