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Review
. 2021 Aug 9;10(8):2032.
doi: 10.3390/cells10082032.

Immune Microenvironment Landscape in CNS Tumors and Role in Responses to Immunotherapy

Hinda Najem  1 , Mustafa Khasraw  2 , Amy B Heimberger  1
Affiliations
Review

Immune Microenvironment Landscape in CNS Tumors and Role in Responses to Immunotherapy

Hinda Najem et al. Cells. .

Abstract

Despite the important evolution of immunotherapeutic agents, brain tumors remain, in general, refractory to immune therapeutics. Recent discoveries have revealed that the glioma microenvironment includes a wide variety of immune cells in various states that play an important role in the process of tumorigenesis. Anti-tumor immune activity may be occurring or induced in immunogenic hot spots or at the invasive edge of central nervous system (CNS) tumors. Understanding the complex heterogeneity of the immune microenvironment in gliomas will likely be the key to unlocking the full potential of immunotherapeutic strategies. An essential consideration will be the induction of immunological effector responses in the setting of the numerous aspects of immunosuppression and evasion. As such, immune therapeutic combinations are a fundamental objective for clinical studies in gliomas. Through immune profiling conducted on immune competent murine models of glioma and ex vivo human glioma tissue, we will discuss how the frequency, distribution of immune cells within the microenvironment, and immune modulatory processes, may be therapeutically modulated to lead to clinical benefits.

Keywords: CNS metastasis; T cells; glioma; immune checkpoints; immune composition; immune therapy; tumor associated macrophages/microglia; tumor microenvironment.

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Conflict of interest statement

M.K. reports personal fees from Ipsen, Pfizer Roche, and Jackson Laboratory for Genomic Medicine and research funding paid to his institution from Specialized Therapeutics, all outside the submitted work. Research funding from AbbVie and Bristol-Myers Squibb were paid to his institution for glioblastoma research. A.B.H. serves on the advisory boards of Caris Life Sciences and WCG Oncology, receives royalties on licensed intellectual property from Celldex Therapeutics and DNAtrix, and receives research support from Celularity, Carthera, Codiak, and Moleculin. The other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Immunosuppressive cross-talk between the immune system and glioma tumor cells. This figure summarizes the different immune checkpoints and cellular pathways associated with T cell exhaustion and inducing the immunosuppressive phenotype of antigen presenting cells (APC). Expression of CTLA-4 immune checkpoint on the T cell surface and its binding to B7 (CD80/CD86) on the APC surface, competes with CD28 thereby blocking T cell activation. In addition, the expression and upregulation of various immune checkpoints such as PD-1, TIM-3, and LAG-3 on the T cell surface triggered by repeated exposures to tumor antigens induces T cell exhaustion. Upregulation of immune checkpoints on immune and glioma cells can be induced by the upregulation of nuclear p-STAT3 known to be a molecular hub for the induction of immunosuppression. pSTAT3 downregulates the major histocompatibility II (MHC II) on the APC surface and induces the secretion of immunosuppressive cytokines like TGF-β, IL-10, and IL-23 (known to shift T cells differentiation to T-regs) that inhibit T cell activation and create an immunosuppressive environment. Glioma cells can express CD47 that binds to the SIRPα receptor on the APC surface thereby impeding phagocytosis. The cGAS-STING pathway senses DNA in the cytoplasm thereby stimulating the immune system by secretion of pro-inflammatory INF-γ favorizing immune cells activation and a macrophage pro-inflammatory phenotype shift. The presence of both CD39 and CD73 in the TME triggers the production of adenosine which binds to the A2aR receptor expressed on the surface of the immune cells thereby inducing immunosuppressive pathways rendering the immune system tumor protective.
Figure 2
Figure 2
Summary of the immunosuppressive role of pSTAT3 in the innate and adaptive immune systems. The innate immune system includes tumor-associated macrophages (TAMs) and dendritic cells (DCs); whereas the adaptive immune system includes T cells. The upregulation of pSTAT3 in the cell nucleus due to various stimuli leads to activation and inhibition of different pathways. In TAMs, increase in pSTAT3 induces impairment of phagocytosis, increases secretion of immunosuppressive cytokines like IL-10, TGFβ-1, and IL-23, and it also induces the expression of PD-L1 on TAMs and DCs. In DCs, pSTAT3 inhibits maturation and leads to a decrease in major histocompatibility II (MHC-II) and co-stimulatory molecules CD80/CD86 expression on the cell surface. In addition, it leads to a decrease in DCs secretion of IL-12 necessary for T cell activation. Finally, the expression of pSTAT3 in T cells leads to effector response inhibition and induction of Tregs by upregulating FOXP3 nuclear expression, thereby leading to a decrease in the secretion of INF-γ and other pro-inflammatory cytokines.
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