Abstract
The central nervous system (CNS) possesses powerful local and global immunosuppressive capabilities that modulate unwanted inflammatory reactions in nervous tissue. These same immune-modulatory mechanisms are also co-opted by malignant brain tumors and pose a formidable challenge to brain tumor immunotherapy. Routes by which malignant gliomas coordinate immunosuppression include the mechanical and functional barriers of the CNS; immunosuppressive cytokines and catabolites; immune checkpoint molecules; tumor-infiltrating immune cells; and suppressor immune cells. The challenges to overcoming tumor-induced immunosuppression, however, are not unique to the brain, and several analogous immunosuppressive mechanisms also exist for primary tumors outside of the CNS. Ultimately, the immune responses in the CNS are linked and complementary to immune processes in the periphery, and advances in tumor immunotherapy in peripheral sites may therefore illuminate novel approaches to brain tumor immunotherapy, and vice versa.
Highlights
Biology, Poland Justin Lathia, Cleveland Clinic, USA Federica Barbieri, University of Genova, Italy Alex Yee-Chen Huang, Case Western Reserve University School of Medicine, USA Derek Alan Wainwright, Northwestern University Feinberg School of Medicine, USA
Administration of anti-TGF-β antibody in vitro blocked conversion of Tconv to the Treg phenotype, and in vivo administration of anti-TGF-β antibody in mice implanted with renal cell carcinoma reduced tumor burden, decreased numbers of circulating FOXP3+ CD25+ CD4+ cells in peripheral blood, and removed the immunosuppressive capabilities of FOXP3+ CD25+ CD4+ T cells [283]
At least five distinct subpopulations of tumor-associated myeloid cells (TAMCs) have been identified, including monocyte-derived tumor-associated macrophages (TAMs); angiogenic monocytes; immature, immunosuppressive myelomonocytic cells known as myeloid-derived suppressor cells (MDSCs); tumor-associated neutrophils (TANs); as well as microglia within the central nervous system (CNS) [87]
Summary
Contrary to common perceptions of central nervous system (CNS) “immune privilege,” the brain can elicit vigorous immune-stimulatory as well as immunosuppressive responses, the determinants of which are highly contextual. Understanding the determinants and mechanisms of both the stimulatory and suppressive responses may help elucidate novel immune-based strategies for brain tumor immunotherapy. We will discuss routes of glioma-mediated immunosuppression, including mechanical and functional barriers of the CNS, immunosuppressive cytokines, immune checkpoint molecules, tumor-infiltrating immune cells, and suppressor immune cells (Table 1). We will look to analogous immune-modulatory mechanisms observed in other sites of the body, as discoveries made at CNS and non-CNS sites are complementary and relevant to therapeutic development for tumors at all sites [1]
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