Regulation of intercellular biomolecule transfer–driven tumor angiogenesis and responses to anticancer therapies

Lu, Zhen; Ortiz, Angélica; Verginadis, Ioannis I.; Peck, Amy R.; Zahedi, Farima; Cho, Christina; Yu, Pengfei; DeRita, Rachel M.; Zhang, Hongru; Kubanoff, Ryan; Sun, Yeying; Yaspan, Andrew T; Krespan, Elise; Beiting, Daniel P.; Radælli, Enrico; Ryeom, Sandra; Diehl, J. Alan; Rui, Hallgeir; Koumenis, Constantinos; Fuchs, Serge Y.

doi:10.1172/jci144225

Cited by 16 publications

(13 citation statements)

References 68 publications

(91 reference statements)

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“…Other studies have revealed that melanoma-derived extracellular vesicles (TEV) reduced the expression of Ch25h in normal cells, and targeting Ch25h or reducing 25HC promoted TEV uptake to accelerate tumor metastases 57 . And knockout Ch25h in endothelial cells could stimulate angiogenesis for tumor growth 58 . In this study, we found that TEM including lactic Acid, Acidic pH and IL4/IL13 could enhance Ch25h expression and lead to 25HC accumulation in TAMs.…”

Section: Discussionmentioning

confidence: 99%

25-Hydroxycholesterol Regulates Lysosome AMPK Activation and Metabolism Reprograming to Educate Immunosuppressive Macrophages

Wang

Xiao

Wang

et al. 2022

Preprint

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Different macrophage subsets exhibit anti-tumor or immunosuppression to regulate tumor progression. Cholesterol metabolism is vital to manipulate macrophage function. Here, we screened cholesterol enzymes and metabolites in three types of immunosuppressive macrophages, which all upregulated cholesterol-25-hydroxylase (Ch25h) expression to cause 25-hydroxycholesterol (25HC) accumulation. scRNA-seq data confirmed that MARCO+ and LYVE1+ macrophage subsets from various human cancers were Ch25hhigh subsets, correlated to lower survival rates. TEM including lactic Acid, Acidic pH and IL4/IL13 enhanced Ch25h expression, and targeting Ch25h abrogated macrophage immunosuppressive function to convert cold tumor into hot tumor, which also synergized with anti-PD1 therapy to improve antitumor efficacy. Critically, 25HC accumulation in lysosome acted as a novel AMPKα agonist, which enhances mitochondrial function and oxidative phosphorylation. We therefore propose Ch25h as an immunometabolic checkpoint and a drug target for tumor immunotherapy, which manipulates macrophage polarization and reshapes TME.

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Section: Discussionmentioning

confidence: 99%

25-Hydroxycholesterol Regulates Lysosome AMPK Activation and Metabolism Reprograming to Educate Immunosuppressive Macrophages

Wang

Xiao

Wang

et al. 2022

Preprint

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“…The other 8 TKIs, that showed promising antitumour activity preclinically, failed in the clinic. For example, the multi-kinase inhibitor sunitinib, when tested as monotherapy on CRC cell lines and in mice, resulted in strong anti-tumour activities [35]. However, in a phase II clinical trial it did not demonstrate a meaningful single-agent objective response rate (ORR) in patients with mCRC refractory to standard chemotherapy [36].…”

Section: Tkis As Monotherapymentioning

confidence: 99%

Lost in translation: Revisiting the use of tyrosine kinase inhibitors in colorectal cancer

Iyer¹,

Erp²,

Tauriello³

et al. 2022

Cancer Treatment Reviews

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“…008068) mice were purchased from The Jackson Laboratory. The conditional Ch25h allele (Ch25h f/f ) was created as previously described 71 . These mice are in the process of being donated to the Jackson Laboratory (future Stock No.…”

Section: Animal Studiesmentioning

confidence: 99%

“…This enzyme catalyzes production of 25-hydroxycholesterol (25HC), which suppresses cholesterol synthesis and affects several important immune pathways 30 . 25HC also acts to inhibit fusion of lipid membranes [31][32][33] ; this property of 25HC is likely to support its activity in suppressing the uptake of the tumor-derived extracellular vesicles, which promote intratumoral angiogenesis and metastasis 33,34 .…”

mentioning

confidence: 99%

Tumor factors stimulate lysosomal degradation of tumor antigens and undermine their cross-presentation in lung cancer

Chen

et al. 2022

Nat Commun

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Activities of dendritic cells (DCs) that present tumor antigens are often suppressed in tumors. Here we report that this suppression is induced by tumor microenvironment-derived factors, which activate the activating transcription factor-3 (ATF3) transcription factor and downregulate cholesterol 25-hydroxylase (CH25H). Loss of CH25H in antigen presenting cells isolated from human lung tumors is associated with tumor growth and lung cancer progression. Accordingly, mice lacking CH25H in DCs exhibit an accelerated tumor growth, decreased infiltration and impaired activation of intratumoral CD8+ T cells. These mice do not establish measurable long-term immunity against malignant cells that undergo chemotherapy-induced immunogenic cell death. Mechanistically, downregulation of CH25H stimulates membrane fusion between endo-phagosomes and lysosomes, accelerates lysosomal degradation and restricts cross-presentation of tumor antigens in the intratumoral DCs. Administration of STING agonist MSA-2 reduces the lysosomal activity in DCs, restores antigen cross presentation, and increases therapeutic efficacy of PD-1 blockade against tumour challenge in a CH25H-dependent manner. These studies highlight the importance of downregulation of CH25H in DCs for tumor immune evasion and resistance to therapy.

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Regulation of intercellular biomolecule transfer–driven tumor angiogenesis and responses to anticancer therapies

Cited by 16 publications

References 68 publications

25-Hydroxycholesterol Regulates Lysosome AMPK Activation and Metabolism Reprograming to Educate Immunosuppressive Macrophages

25-Hydroxycholesterol Regulates Lysosome AMPK Activation and Metabolism Reprograming to Educate Immunosuppressive Macrophages

Lost in translation: Revisiting the use of tyrosine kinase inhibitors in colorectal cancer

Tumor factors stimulate lysosomal degradation of tumor antigens and undermine their cross-presentation in lung cancer

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