Brain immunology and immunotherapy in brain tumours

Abstract

Gliomas, the most common malignant primary brain tumours, remain universally lethal. Yet, seminal discoveries in the past 5 years have clarified the anatomy, genetics and function of the immune system within the central nervous system (CNS) and altered the paradigm for successful immunotherapy. The impact of standard therapies on the response to immunotherapy is now better understood, as well. This new knowledge has implications for a broad range of tumours that develop within the CNS. Nevertheless, the requirements for successful therapy remain effective delivery and target specificity, while the dramatic heterogeneity of malignant gliomas at the genetic and immunological levels remains a profound challenge.

Fig. 1. Immune privilege in the brain.

Historically, the central nervous system (CNS) was considered to be isolated immunologically. Features that contributed to this understanding were the presence of tight junctions in the blood–brain barrier, the absence of a classic lymphatic drainage system, and empirical data showing the ability of the CNS to target foreign tissues with minimal inflammatory responses. However, today the concept of immune privilege has been partially redefined. It is now clear that there are functional lymphatic vessels in the CNS, and that antigen-presenting cells (APCs) of varied types exist within the CNS, including microglia, macrophages, astrocytes and classic APCs such as dendritic cells (DCs). It is now known that the CNS is not isolated from activated T cells, which can patrol these compartments in an unrestricted manner, and that CNS antigens can be presented locally or in the draining cervical lymph nodes. While the immune system in the CNS remains different, it is not incapable. CSF, cerebrospinal fluid.

Fig. 2. Immunosuppressive mediators and therapeutic targets in the brain tumour microenvironment.

Tumour-associated macrophages (TAMs) play a central role in the brain tumour microenvironment. TAMs arise from circulating monocytes and, to a lesser extent, microglia. The recruitment of monocytes and their differentiation into TAMs is supported by the chemokine CC-chemokine ligand 2 (CCL2) and the cytokine colony-stimulating factor 1 (CSF1). TAMs can be activated towards either an inflammatory or an anti-inflammatory phenotype. Inflammatory TAMs inhibit tumour growth and support T cell-mediated tumour killing through the production of inflammatory cytokines such as IL-12 and tumour necrosis factor (TNF). Anti-inflammatory TAMs and astrocytes produce IL-10 and transforming growth factor β (TGFβ), both of which inhibit T cell effector functions and inflammatory TAM activities[45]. Anti-inflammatory TAMs and microglia produce arginase, which inhibits T cells through arginine depletion from the tumour microenvironment. Gliomas produce indolamine 2,3-dioxygenase (IDO), which acts to recruit regulatory T (T_reg) cells and inhibit effector T cells through tryptophan depletion. Potential therapeutic strategies to target these immunosuppressive pathways are shown in purple.

Fig. 3. Epigenetic events play a key role in modulating immune responses to brain tumours.

a | Isocitrate dehydrogenase 1 (IDH1) mutations in glioma can cause down-regulation of leukocyte chemotaxis, resulting in repression of the tumour-associated immune system. An IDH mutation results in the generation of the oncometabolite 2-hydroxyglutarate (2HG; via conversion from α-ketoglutarate), which in turn represses signal transducer and activator of transcription 1 (STAT1) expression, leading to reduced expression of interferon-γ (IFNγ)-inducible chemokines, including CXC chemokine ligand 9 (CXCL9) and CXCL10. As a consequence, IDH-mutated tumours suppress the infiltration and accumulation of T cells at tumour sites. b | In mice bearing IDH-mutated glioma, these effects can be reversed through pharmacological inhibition with IDH-C35, a specific inhibitor of mutant IDH. Adapted from ref.[228], Springer Nature Limited.

Fig. 4. Chimeric antigen receptor T cell immunotherapy in brain tumours.

Chimeric antigen receptor (CAR) T cells have been used to target tumour-specific and tumour-associated antigens in malignant gliomas. There appears to be no impediment to these cells reaching and killing target antigen-expressing tumour cells in the central nervous system (CNS). The challenge remains for these highly specific and potent agents to target antigen-negative tumour cells directly within these highly heterogeneous tumours. APC, antigen-presenting cell; DAMP, damage-associated molecular pattern; DC, dendritic cell; EGFRvIII, epidermal growth factor receptor variant III; IFNγ, interferon-γ; LN, lymph node; MHC-I, major histocompatibility complex class I; T_c, cytotoxic T cell; TCR, T cell receptor; T_H, T helper cell; TNF, tumour necrosis factor. Adapted from ref.[229] (Johnson, L. A., Sanchez-Perez, L., Suryadevara, C. M. & Sampson, J. H. Chimeric antigen receptor engineered T cells can eliminate brain tumors and initiate long-term protection against recurrence. Oncoimmunology 3, e944059 (2014)), with permission of the publisher (Taylor & Francis Ltd, http://www.tandfonline.com).