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Abstract Despite the robust homeostasis of the brain, its high prevalence of tumor metastasis is intriguing and the underlying mechanism may contribute to the development of novel therapies. Microglia have emerged as promising therapeutic targets due to their role in brain parenchymal homeostasis. However, with evidence for both pro- and anti-tumorigenic functions, their role in brain metastasis (BrM) remains unclear. Here, we show that the microglial response to tumor cells within a single host is heterogeneous and can alter tumor fate. Single-cell RNA sequencing was performed on five surgically resected metastatic brain tumors, and the transcriptome of tumor-associated microglia was extracted by single-cell variational inference (scVI). Evidence for the coexistence of cytokine-secreting and angiogenesis-supporting subsets, as well as subsets associated with phagocytosis and antigen presentation, within each tumor sample was determined. To demonstrate the intra-tumoral functional heterogeneity of tumor-associated microglia, we established a metastatic brain tumor model that allows us to visualize the metastatic process and the dynamic microglial response in vivo by injecting mCherry-tagged allogeneic cancer cells into the internal carotid artery of CX3CR1-EGFP mice. Metastasis formation was suppressed in microglia-depleted mice, identifying a dominant microglial response that promotes tumor growth. However, continuous in vivo imaging of the BrM model revealed tumor-eradicating anti-tumor microglia coexisting with pro-tumor microglia in the same host. The transcriptome of anti-tumor microglia supported that they are enriched for phagocytosis, antigen processing and antigen presentation genes. The subset was identified in microglia extracted from human samples. We then examined the immune checkpoint of microglial phagocytosis in the tumor transcriptome and identified Cd24a and Cd47. Simultaneous deletion of both genes in cancer cells enhanced microglial phagocytosis, reduced tumor volume and improved survival, and rescue of both genes reversed these anti-tumor effects. The microglial dependency was addressed by microglial depletion experiments, and the anti-tumor effects were reproducible in nude mice lacking mature T cells. These results suggest that there are distinct immune cell subtypes that respond to lung tumor metastases in the brain and either promote tumor growth or inhibit metastasis through phagocytosis. Furthermore, anti-tumor activity in mouse models can be enhanced by genetic deletion of Cd24a and Cd47 in tumor cells, which regulate phagocytosis by microglia. Citation Format: Takahiro Tsuji, Haruka Hirose, Mariko Shindo, Rahadian Yudo Hartantyo, Yutaro Saito, Kazutaka Hosoya, Hiroshi Yoshida, Daisuke Kato, Akihiko Yoshizawa, Yoshiki Arakawa, Hiroaki Ozasa, Toyohiro Hirai, Hiroaki Wake. Enhanced microglial phagocytosis of metastatic brain tumor cells with Cd24a/Cd47 depletion abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4140.
Tsuji et al. (Fri,) studied this question.