The relationship between chronic psychological stress and tumorigenesis has been well defined in epidemiological studies;however, the underlying mechanism remains underexplored. In this study, we discovered that impai...The relationship between chronic psychological stress and tumorigenesis has been well defined in epidemiological studies;however, the underlying mechanism remains underexplored. In this study, we discovered that impaired macrophage phagocytosis contributed to the psychological stressevoked tumor susceptibility, and the stress hormone glucocorticoid(GC) was identified as a principal detrimental factor. Mechanistically, GC disturbed the balance of the "eat me" signal receptor(low-density lipoprotein receptor-related protein-1, LRP1) and the "don’t eat me" signal receptor(signal regulatory protein alpha, SIRPa). Further analysis revealed that GC led to a direct, glucocorticoid receptor(GR)-dependent trans-repression of LRP1 expression, and the repressed LRP1, in turn, resulted in the elevatedgene level of SIRPa by down-regulating mi RNA-4695-3 p. These data collectively demonstrate that stress induces the imbalance of the LRP1/SIRPa axis and entails the disturbance of tumor cell clearance by macrophages. Our findings provide the mechanistic insight into psychological stress-evoked tumor susceptibility and indicate that the balance of LRP1/SIRPa axis may serve as a potential therapeutic strategy for tumor treatment.展开更多
The potential of macrophage-mediated phagocytosis as a cancer treatment is promising.Blocking the CD47–SIRPαinteraction with a CD47-specific antibody significantly enhances macrophage phagocytosis.However,concerns r...The potential of macrophage-mediated phagocytosis as a cancer treatment is promising.Blocking the CD47–SIRPαinteraction with a CD47-specific antibody significantly enhances macrophage phagocytosis.However,concerns regarding their toxicity to nontumor cells remain substantial.Here,we engineered chimeric antigen receptor macrophages(CAR-Ms)by fusing a humanized single-chain variable fragment with FcγRIIa and integrating short hairpin RNA to silence SIRPα,thereby disrupting the CD47–SIRPαsignaling pathway.These modified CAR-shSIRPα-M cells exhibited an M1-like phenotype,superior phagocytic function,substantial cytotoxic effects on HER2-positive tumor cells,and the ability to eliminate patient-derived organoids.In vivo,CAR-M cells significantly inhibited tumor growth and prolonged survival in tumor-bearing mice.Notably,CAR-shSIRPα-M cells enhanced cytotoxic T-cell infiltration into tumors,thereby enhancing the antitumor response in both the humanized immune system mouse model and immunocompetent mice.Mechanistically,SIRPαinhibition activated inflammatory pathways and the cGAS-STING signaling cascade in CAR-M cells,leading to increased production of proinflammatory cytokines,reactive oxygen species,and nitric oxide,thereby enhancing their antitumor effects.These findings underscore the potential of SIRPαinhibition as a novel strategy to increase the antitumor efficacy of CAR-M cells in cancer immunotherapy,particularly against solid tumors.展开更多
Group-2 innate lymphoid cells(ILC2)are part of a growing family of innate lymphocytes known for their crucial role in both the development and exacerbation of allergic asthma.The activation and function of ILC2s are r...Group-2 innate lymphoid cells(ILC2)are part of a growing family of innate lymphocytes known for their crucial role in both the development and exacerbation of allergic asthma.The activation and function of ILC2s are regulated by various activating and inhibitory molecules,with their balance determining the severity of allergic responses.In this study,we aim to elucidate the critical role of the suppressor molecule signal regulatory protein alpha(SIRPα),which interacts with CD47,in controlling ILC2-mediated airway hyperreactivity(AHR).Our data indicate that activated ILC2s upregulate the expression of SIRPα,and the interaction between SIRPαand CD47 effectively suppresses both ILC2 proliferation and effector function.To evaluate the function of SIRPαin ILC2-mediated AHR,we combined multiple approaches including genetically modified mouse models and adoptive transfer experiments in murine models of allergen-induced AHR.Our findings suggest that the absence of SIRPαleads to the overactivation of ILC2s.Conversely,engagement of SIRPαwith CD47 reduces ILC2 cytokine production and effectively regulates ILC2-dependent AHR.Furthermore,the SIRPα-CD47 axis modulates mitochondrial metabolism through the JAK/STAT and ERK/MAPK signaling pathways,thereby regulating NF-κB activity and the production of type 2 cytokines.Additionally,our studies have revealed that SIRPαis inducible and expressed on human ILC2s,and administration of human CD47-Fc effectively suppresses the effector function and cytokine production.Moreover,administering human CD47-Fc to humanized ILC2 mice effectively alleviates AHR and lung inflammation.These findings highlight the promising therapeutic potential of targeting the SIRPα-CD47 axis in the treatment of ILC2-dependent allergic asthma.展开更多
基金supported,in part,by National Natural Science Foundation of China(grant numbers 81673709,82004231,U1801284 and 81873209)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(grant number 2017BT01Y036,China)and GDUPS(2019,China)+5 种基金Guangdong Science and Technology Foundation for Distinguished Young Scholars(grant number 2017A030306004,China)Science and Technology Program of Guangzhou(grant numbers 201903010062 and 202102010116,China)Fellowship of China Postdoctoral Science Foundation(grant number 2020M683204,China)Guangdong Basic and Applied Basic Research Fund(grant number 2020A1515110388,China)Fundamental Research Funds for the Central Universities(grant number 21620448,China)support of K.C.Wong Education Foundation。
文摘The relationship between chronic psychological stress and tumorigenesis has been well defined in epidemiological studies;however, the underlying mechanism remains underexplored. In this study, we discovered that impaired macrophage phagocytosis contributed to the psychological stressevoked tumor susceptibility, and the stress hormone glucocorticoid(GC) was identified as a principal detrimental factor. Mechanistically, GC disturbed the balance of the "eat me" signal receptor(low-density lipoprotein receptor-related protein-1, LRP1) and the "don’t eat me" signal receptor(signal regulatory protein alpha, SIRPa). Further analysis revealed that GC led to a direct, glucocorticoid receptor(GR)-dependent trans-repression of LRP1 expression, and the repressed LRP1, in turn, resulted in the elevatedgene level of SIRPa by down-regulating mi RNA-4695-3 p. These data collectively demonstrate that stress induces the imbalance of the LRP1/SIRPa axis and entails the disturbance of tumor cell clearance by macrophages. Our findings provide the mechanistic insight into psychological stress-evoked tumor susceptibility and indicate that the balance of LRP1/SIRPa axis may serve as a potential therapeutic strategy for tumor treatment.
基金funded by grants from the National Natural Science Foundation of China(grant number 82073361)the State Key Laboratory of Cancer Biology Project(grant number CBSKL2022ZZ21)+1 种基金the Key R&D Plan of Shaanxi Province(grant number 2023-YBSF-667)the Xi’an Municipal Health Commission(grant number 2022 ms06).
文摘The potential of macrophage-mediated phagocytosis as a cancer treatment is promising.Blocking the CD47–SIRPαinteraction with a CD47-specific antibody significantly enhances macrophage phagocytosis.However,concerns regarding their toxicity to nontumor cells remain substantial.Here,we engineered chimeric antigen receptor macrophages(CAR-Ms)by fusing a humanized single-chain variable fragment with FcγRIIa and integrating short hairpin RNA to silence SIRPα,thereby disrupting the CD47–SIRPαsignaling pathway.These modified CAR-shSIRPα-M cells exhibited an M1-like phenotype,superior phagocytic function,substantial cytotoxic effects on HER2-positive tumor cells,and the ability to eliminate patient-derived organoids.In vivo,CAR-M cells significantly inhibited tumor growth and prolonged survival in tumor-bearing mice.Notably,CAR-shSIRPα-M cells enhanced cytotoxic T-cell infiltration into tumors,thereby enhancing the antitumor response in both the humanized immune system mouse model and immunocompetent mice.Mechanistically,SIRPαinhibition activated inflammatory pathways and the cGAS-STING signaling cascade in CAR-M cells,leading to increased production of proinflammatory cytokines,reactive oxygen species,and nitric oxide,thereby enhancing their antitumor effects.These findings underscore the potential of SIRPαinhibition as a novel strategy to increase the antitumor efficacy of CAR-M cells in cancer immunotherapy,particularly against solid tumors.
基金supported by R01 HL144790,R01 HL151493,R01 AI145813,R01 AI169687,R01 HL151769,R01 HL 159804 grant from the National Institutes of Health,Public Health Service(O.A.).Schematic diagrams(Figure 4E and Figure 6K)were designed with Biorender.com.
文摘Group-2 innate lymphoid cells(ILC2)are part of a growing family of innate lymphocytes known for their crucial role in both the development and exacerbation of allergic asthma.The activation and function of ILC2s are regulated by various activating and inhibitory molecules,with their balance determining the severity of allergic responses.In this study,we aim to elucidate the critical role of the suppressor molecule signal regulatory protein alpha(SIRPα),which interacts with CD47,in controlling ILC2-mediated airway hyperreactivity(AHR).Our data indicate that activated ILC2s upregulate the expression of SIRPα,and the interaction between SIRPαand CD47 effectively suppresses both ILC2 proliferation and effector function.To evaluate the function of SIRPαin ILC2-mediated AHR,we combined multiple approaches including genetically modified mouse models and adoptive transfer experiments in murine models of allergen-induced AHR.Our findings suggest that the absence of SIRPαleads to the overactivation of ILC2s.Conversely,engagement of SIRPαwith CD47 reduces ILC2 cytokine production and effectively regulates ILC2-dependent AHR.Furthermore,the SIRPα-CD47 axis modulates mitochondrial metabolism through the JAK/STAT and ERK/MAPK signaling pathways,thereby regulating NF-κB activity and the production of type 2 cytokines.Additionally,our studies have revealed that SIRPαis inducible and expressed on human ILC2s,and administration of human CD47-Fc effectively suppresses the effector function and cytokine production.Moreover,administering human CD47-Fc to humanized ILC2 mice effectively alleviates AHR and lung inflammation.These findings highlight the promising therapeutic potential of targeting the SIRPα-CD47 axis in the treatment of ILC2-dependent allergic asthma.
