Microglia-Centered Combinatorial Strategies Against Glioblastoma

Abstract

Tumor-associated microglia (MG) and macrophages (MΦ) are important components of the glioblastoma (GBM) immune tumor microenvironment (iTME). From the recent advances in understanding how MG and GBM cells evolve and interact during tumorigenesis, we emphasize the cooperation of MG with other immune cell types of the GBM-iTME, mainly MΦ and T cells. We provide a comprehensive overview of current immunotherapeutic clinical trials and approaches for the treatment of GBM, which in general, underestimate the counteracting contribution of immunosuppressive MG as a main factor for treatment failure. Furthermore, we summarize new developments and strategies in MG reprogramming/re-education in the GBM context, with a focus on ways to boost MG-mediated tumor cell phagocytosis and associated experimental models and methods. This ultimately converges in our proposal of novel combinatorial regimens that locally modulate MG as a central paradigm, and therefore may lead to additional, long-lasting, and effective tumoricidal responses.

Keywords: glioblastoma; glioma- associated macrophages; glioma-associated microglia; immune tumor microenvironment; immunotherapy; microglia modulation.

Figure 1

Classification of GBM based on histological, clinical, genetic, -omic, and immune features. IDH^mut and IDH^wt glioma subtypes are indicated in shades of blue and red, respectively. Arrows indicate tumor progression. The definition of iTME composition is described in the relevant publications. Median survival of ODG and diffuse astrocytoma is based on WHO grade II (, –, –19).

Figure 2

Combinatorial approaches of local MG modulation and other treatment modalities against GBM. Means of local MG modulation (upper right): MG can be targeted locally beyond the BBB by various approaches to influence MG phagocytosis, enhance antigen presentation, and revert generalized immunosuppression. Prominent potential means to locally modulate MG include anti-CD47 or anti-Siglec treatments, intratumoral desialylation, application of pro-inflammatory cytokines, “reprogramming” by blocking CSF1 signaling, or addition of immunomodulatory nanoparticles. Some of these modalities would also interfere with infiltrating BMDMs (e.g., anti-CCL2 blockade). Overall, this would enable other tumor specific or immunotherapeutic regimens to exert their antitumorigenic activity. Combinatorial approaches with MG modulation: Personalized vaccination, oncolytic viral therapy, or bacterial based approaches: the effect of tumor-specific vaccinations, oncolytic viruses, or tumor-targeting bacteria might be significantly enhanced when tumor-associated MG is reverted to a less immunosuppressive phenotype. MG modulation + tumor-targeting CAR T cell therapy: combining MG modulation with tumor antigen-specific CAR T cell therapy poses another way to circumvent current obstacles in GBM therapy. Local application of MG modulation and tumor-specific CAR T cells might result in better GBM control. Novel CAR T products could combine MG modulation (e.g., by reprogramming MG and targeting the tumor at once). MG modulation + chemotherapy or targeted treatments: tumor cells respond to established chemotherapy with increased expression of “eat-me” signals. Combinatorial strategies of already established chemotherapies with inducers of MG phagocytosis could improve treatment responses. MG modulation + T cell checkpoint therapy: this dual strategy of targeting the major players of the GBM-iTME—MG—and facilitating an intratumoral T cell response in addition to a putative MG-mediated T cell response might boost tumor regression. Further, the thorough analysis of tumor-phagocytosing MG vs. non-phagocytosing MG, their MHC molecules and linked, presented antigens, could lead to the discovery of novel tumor antigens and result in potential vaccination candidates. MG modulation + angiogenesis inhibition: anti-VEGFR treatment serves as a salvage therapy in recurrent GBM. Additional MG activation might prevent development of early resistance. MG modulation + radiation therapy: in line with chemotherapy, radiation therapy enhances immune responses and upregulates “eat-me” signals on tumor cells. Additional MG modulation could increase efficacy and long term treatment responses. Created with Biorender.com.