Aging · 2024
Activation of Notch-1 signaling pathway in macrophages to secrete PD-L1 and regulate cytotoxicity of CAR-T cells in diffuse large B-cell lymphoma.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Li Weijing, Wu Lili, Huang Chen, Ma Hongqing, Wang Lianjing, Liu Wei, Liu Lihong
Аннотация
OBJECTIVE: To investigate the mechanism of action of the Notch-1/IRE1/XBP1s signaling pathway in diffuse large B-cell lymphoma (DLBCL).
METHODS: The expressions of relevant proteins were detected by Western blotting. The effect of myeloid-specific knockout of Notch-1 on lymphoma progression was observed by mouse tumor transplantation and imaging. The apoptosis of chimeric antigen receptor T-cell therapy (CAR-T) cells were detected by flow cytometry, and the proliferation of CAR-T cells was detected by wound healing assay and cell counting kit-8 (CCK8) assay.
RESULTS: Lymphoma cells mediated the Notch-1 signaling pathway in bone marrow-derived macrophages and promoted the activation of STAT3 and STAT6 in bone marrow-derived macrophages. Myeloid-specific knockout of Notch-1 could inhibit the progression of lymphoma. Lymphoma cells enhanced the expression of p-PERK, p-IRE1α, ATF6, IL-6, IL-4, p-AKT, CD9, CD63 and PD-L1 in bone marrow-derived macrophages by mediating the Notch-1 signaling pathway. Knockout of Notch-1 in macrophages alleviated, to some extent, the suppression of killing activity of CAR-T cells, while activation of Notch-1 in macrophages inhibited proliferation and promoted apoptosis of CAR-T cells. The PD-L1 antibody significantly restored the cytotoxicity and proliferation of CAR-T cells, and inhibited their apoptosis.
CONCLUSION: Activation of the Notch-1/IRE1/XBP1s signaling pathway in myeloid macrophages promotes the secretion of IL-6 and IL-4 as well as PD-L1, thereby inhibiting the activity and proliferation of CAR-T cells and promoting their apoptosis.
METHODS: The expressions of relevant proteins were detected by Western blotting. The effect of myeloid-specific knockout of Notch-1 on lymphoma progression was observed by mouse tumor transplantation and imaging. The apoptosis of chimeric antigen receptor T-cell therapy (CAR-T) cells were detected by flow cytometry, and the proliferation of CAR-T cells was detected by wound healing assay and cell counting kit-8 (CCK8) assay.
RESULTS: Lymphoma cells mediated the Notch-1 signaling pathway in bone marrow-derived macrophages and promoted the activation of STAT3 and STAT6 in bone marrow-derived macrophages. Myeloid-specific knockout of Notch-1 could inhibit the progression of lymphoma. Lymphoma cells enhanced the expression of p-PERK, p-IRE1α, ATF6, IL-6, IL-4, p-AKT, CD9, CD63 and PD-L1 in bone marrow-derived macrophages by mediating the Notch-1 signaling pathway. Knockout of Notch-1 in macrophages alleviated, to some extent, the suppression of killing activity of CAR-T cells, while activation of Notch-1 in macrophages inhibited proliferation and promoted apoptosis of CAR-T cells. The PD-L1 antibody significantly restored the cytotoxicity and proliferation of CAR-T cells, and inhibited their apoptosis.
CONCLUSION: Activation of the Notch-1/IRE1/XBP1s signaling pathway in myeloid macrophages promotes the secretion of IL-6 and IL-4 as well as PD-L1, thereby inhibiting the activity and proliferation of CAR-T cells and promoting their apoptosis.