Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma

Wang, Shiqun; Yan, Wei; Kong, Lingkai; Zuo, Shuguang; Wu, Jingyi; Zhu, Chunxiao; Huang, Haiyang; He, Bohao; Dong, Jie; Wei, Jiwu

doi:10.1038/s41467-023-39683-z

Cited by 20 publications

(4 citation statements)

References 71 publications

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“…Moreover, KRT14 expression has been implicated in MHC class II presentation in breast cancer [ 35 ], suggesting that down-regulation of KRT14 in TNBC could result in increased MHC II expression and facilitate the activation of CD4 + T cells. In our previous study [ 49 ], we discovered that the accumulation of cholesterol in tumor-associated macrophages (TAMs) significantly hinders the mitochondrial translation of TAMs, which ultimately impacts their phagocytic function. Conversely, the intratumoral injection of ADV-ApoA1 can reprogram the lipid metabolism of the GBM tumor microenvironment, modulate cholesterol efflux, restore TAMs’ phagocytosis, and reactivate TAM-T cell anti-tumor immunity.…”

Section: Discussionmentioning

confidence: 99%

Oncolytic adenovirus encoding apolipoprotein A1 suppresses metastasis of triple-negative breast cancer in mice

Dong,

Kong,

Wang

et al. 2024

J Exp Clin Cancer Res

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Background Dysregulation of cholesterol metabolism is associated with the metastasis of triple-negative breast cancer (TNBC). Apolipoprotein A1 (ApoA1) is widely recognized for its pivotal role in regulating cholesterol efflux and maintaining cellular cholesterol homeostasis. However, further exploration is needed to determine whether it inhibits TNBC metastasis by affecting cholesterol metabolism. Additionally, it is necessary to investigate whether ApoA1-based oncolytic virus therapy can be used to treat TNBC. Methods In vitro experiments and mouse breast cancer models were utilized to evaluate the molecular mechanism of ApoA1 in regulating cholesterol efflux and inhibiting breast cancer progression and metastasis. The gene encoding ApoA1 was inserted into the adenovirus genome to construct a recombinant adenovirus (ADV-ApoA1). Subsequently, the efficacy of ADV-ApoA1 in inhibiting the growth and metastasis of TNBC was evaluated in several mouse models, including orthotopic breast cancer, spontaneous breast cancer, and human xenografts. In addition, a comprehensive safety assessment of Syrian hamsters and rhesus monkeys injected with oncolytic adenovirus was conducted. Results This study found that dysregulation of cholesterol homeostasis is critical for the progression and metastasis of TNBC. In a mouse orthotopic model of TNBC, a high-cholesterol diet promoted lung and liver metastasis, which was associated with keratin 14 (KRT14), a protein responsible for TNBC metastasis. Furthermore, studies have shown that ApoA1, a cholesterol reverse transporter, inhibits TNBC metastasis by regulating the cholesterol/IKBKB/FOXO3a/KRT14 axis. Moreover, ADV-ApoA1 was found to promote cholesterol efflux, inhibit tumor growth, reduce lung metastasis, and prolonged the survival of mice with TNBC. Importantly, high doses of ADV-ApoA1 administered intravenously and subcutaneously were well tolerated in rhesus monkeys and Syrian hamsters. Conclusions This study provides a promising oncolytic virus treatment strategy for TNBC based on targeting dysregulated cholesterol metabolism. It also establishes a basis for subsequent clinical trials of ADV-ApoA1 in the treatment of TNBC.

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Section: Discussionmentioning

confidence: 99%

Oncolytic adenovirus encoding apolipoprotein A1 suppresses metastasis of triple-negative breast cancer in mice

Dong,

Kong,

Wang

et al. 2024

J Exp Clin Cancer Res

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“…Dysregulated cholesterol metabolism in the glioblastoma microenvironment also promotes tumor progression and immunosuppression. Therefore, targeting the disordered cholesterol metabolism in GBM, Wang et al developed an oncolytic adenovirus loaded with the cholesterol reverse transporter apolipoprotein A1 (ApoA1), for the treatment of GBM, which restores macrophages phagocytosis by manipulating cholesterol efflux and reactivates anti-tumor immunity [ 89 ]. Dong et al found that in GBM, macrophages highly expressed 7-dehydrocholesterol reductase (DHCR7), increased cholesterol biosynthesis, and served as “cholesterol factory” supplying cholesterol for GBM growth.…”

Section: Therapeutic Strategies Targeting Metabolism Between Gams And...mentioning

confidence: 99%

Microglia and macrophage metabolism: a regulator of cerebral gliomas

Deng,

Chen,

Wan

et al. 2024

Cell Biosci

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Reciprocal interactions between the tumor microenvironment (TME) and cancer cells play important roles in tumorigenesis and progression of glioma. Glioma-associated macrophages (GAMs), either of peripheral origin or representing brain-intrinsic microglia, are the majority population of infiltrating immune cells in glioma. GAMs, usually classified into M1 and M2 phenotypes, have remarkable plasticity and regulate tumor progression through different metabolic pathways. Recently, research efforts have increasingly focused on GAMs metabolism as potential targets for glioma therapy. This review aims to delineate the metabolic characteristics of GAMs within the TME and provide a summary of current therapeutic strategies targeting GAMs metabolism in glioma. The goal is to provide novel insights and therapeutic pathways for glioma by highlighting the significance of GAMs metabolism.

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“…It leads to Siglec-10 or PD-1 enhancement, resulting in loss of phagocytic capacity of TAMs. In addition, cholesterol accumulation impaired mitochondrial function in TAMs, and cholesterol-induced mitochondrial damage through the oxidation product 7-ketocholesterol could inhibit the phagocytosis of TAMs.ApoA1-mediated cholesterol efflux from TAMs can reduce mitochondrial damage and restore the phagocytosis of TAMs [ 25 ]. In summary, tumor cells promote cholesterol accumulation in the microenvironment.…”

Section: Reprogramming Of Lipid Metabolism In the Tumor Microenvironmentmentioning

confidence: 99%

Reprogramming of lipid metabolism in the tumor microenvironment: a strategy for tumor immunotherapy

Wu,

Pu,

Wang

et al. 2024

Lipids Health Dis

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Lipid metabolism in cancer cells has garnered increasing attention in recent decades. Cancer cells thrive in hypoxic conditions, nutrient deficiency, and oxidative stress and cannot be separated from alterations in lipid metabolism. Therefore, cancer cells exhibit increased lipid metabolism, lipid uptake, lipogenesis and storage to adapt to a progressively challenging environment, which contribute to their rapid growth. Lipids aid cancer cell activation. Cancer cells absorb lipids with the help of transporter and translocase proteins to obtain energy. Abnormal levels of a series of lipid synthases contribute to the over-accumulation of lipids in the tumor microenvironment (TME). Lipid reprogramming plays an essential role in the TME. Lipids are closely linked to several immune cells and their phenotypic transformation. The reprogramming of tumor lipid metabolism further promotes immunosuppression, which leads to immune escape. This event significantly affects the progression, treatment, recurrence, and metastasis of cancer. Therefore, the present review describes alterations in the lipid metabolism of immune cells in the TME and examines the connection between lipid metabolism and immunotherapy.

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Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma

Cited by 20 publications

References 71 publications

Oncolytic adenovirus encoding apolipoprotein A1 suppresses metastasis of triple-negative breast cancer in mice

Oncolytic adenovirus encoding apolipoprotein A1 suppresses metastasis of triple-negative breast cancer in mice

Microglia and macrophage metabolism: a regulator of cerebral gliomas

Reprogramming of lipid metabolism in the tumor microenvironment: a strategy for tumor immunotherapy

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