查看更多>>摘要：Human umbilical cord mesenchymal stem cells(hUC-MSCs)have shown potential as a therapeutic option for lupus nephritis(LN),particularly in patients refractory to conventional treatments.Despite extensive translational research on MSCs,the precise mechanisms by which MSCs migrate to the kidney and restore renal function remain incompletely understood.Here,we aim to clarify the spatiotemporal characteristics of hUC-MSC migration into LN kidneys and their interactions with host cells in microenvironment.This study elucidates that the migration of hUC-MSCs to the LN kidney is driven by elevated levels of CXCL10,predominantly produced by glomerular vascular endothelial cells through the IFN-γ/IRF1-KPNA4 pathway.Interestingly,the blockade of CXCL10-CXCR3 axis impedes the migration of hUC-MSCs to LN kidney and negatively impacts therapeutic outcomes.Single cell-RNA sequencing analysis underscores the importance of this axis in mediating the regulatory effects of hUC-MSCs on the renal immune environment.Furthermore,hUC-MSCs have been observed to induce and secrete interleukin 4 inducible gene 1(IL4I1)in response to the microenvironment of LN kidney,thereby suppressing Th1 cells.Genetically ablating IL4I1 in hUC-MSCs abolishes their therapeutic effects and prevents the inhibition of CXCR3+Th1 cell infiltration into LN kidneys.This study provides valuable insights into the significant involvement of CXCL10-CXCR3 axis in hUC-MSC migration to the LN kidneys and the subsequent remodeling of renal immune microenvironment.Regulating the CXCL10-CXCR3 axis and IL4I1 secretion may be developed as a novel therapeutic strategy to improve treatment outcomes of LN.
查看更多>>摘要：EphrinB2(erythropoietin-producing hepatoma interactor B2)is a key Eph/ephrin family member,promoting angiogenesis,vasculogenesis,and lymphangiogenesis during embryonic development.However,the role of EphrinB2 in cardiac lymphangiogenesis following myocardial infarction(MI)and the potential molecular mechanism remains to be demonstrated.This study revealed that EphrinB2 prevented ischemic heart post-MI from remodeling and dysfunction by activating the cardiac lymphangiogenesis signaling pathway.Deletion of EphrinB2 impaired cardiac lymphangiogenesis and aggravated adverse cardiac remodeling and ventricular dysfunction post-MI.At the same time,overexpression of EphrinB2 stimulated cardiac lymphangiogenesis which facilitated cardiac infiltrating macrophage drainage and reduced inflammation in the ischemic heart.The beneficial effects of EphrinB2 on improving clearance of inflammatory response and cardiac function were abolished in Lyve1 knockout mice.Mechanistically,EphrinB2 accelerated cell cycling and lymphatic endothelial cell proliferation and migration by activating CDK5 and CDK5-dependent ISL1 nuclear translocation.EphrinB2 enhanced the transcriptional activity of ISL1 at the VEGFR3(FLT4)promoter,and VEGFR3 inhibitor MAZ51 significantly diminished the EphrinB2-mediated lymphangiogenesis and deteriorated the ischemic cardiac function.We uncovered a novel mechanism of EphrinB2-driven cardiac lymphangiogenesis in improving myocardial remodeling and function after MI.
查看更多>>摘要：The mucosal immune response plays a crucial role in the prevention of respiratory viruses.Given the risk of recurrent SARS-CoV-2 infections in the population,the rapid development of next-generation intranasal COVID-19 vaccines with high safety and efficacy is paramount.In the current study,we developed a protein-based intranasal vaccine comprising the XBB.1.5 receptor binding domain(RBD)-derived trimeric recombinant protein(RBDXBB.1.5-HR)and an MF59-like oil-in-water adjuvant.Intranasal administration of RBDXBB.1.5-HR vaccine elicited robust and sustained humoral immune responses in mice and rats,resulting in high levels of neutralizing antibodies against XBB-lineage subvariants,with protection lasting for at least six months.The intranasal RBDXBB.1.5-HR vaccine generated potent mucosal immune responses,characterized by the inductions of tissue-resident T(TRM)cells,local cellular immunity,germinal center,and memory B cell responses in the respiratory tract.The combination of intramuscular and intranasal delivery of the RBDXBB.1.5-HR vaccine demonstrated exceptional systemic and mucosal protective immunity.Furthermore,intranasal delivery of RBDXBB.1.5-HR vaccine as a heterologous booster shot showed more effective boosting effects after mRNA administration compared to homologous vaccination,as evidenced by the induction of superior systemic and extra mucosal immune response.Importantly,the intranasal RBDXBB.1.5-HR vaccine conferred efficient protection against the challenge with authentic EG.5.1 viruses in vivo.These findings identify the intranasal RBDXBB.1.5-HR vaccine as a potential mucosal vaccine candidate for the prevention of SARS-CoV-2 infection.
查看更多>>摘要：The intricate tumor microenvironment presents formidable obstacles to the efficacy of adoptive T cell therapy in the management of solid tumors by limiting the infiltration and inducing exhaustion of the transferred T cells.Here,we developed a bacterial-based adjuvant approach that augments the efficacy of adoptive T-cell therapy for solid tumor treatment.Our study reveals that intratumor injection of E.coli MG1655 normalizes tumor vasculatures and reprograms tumor-associated macrophages into M1 phenotype that produce abundant CCL5,together facilitating tumor infiltration of adoptively transferred T cells.The depletion of tumor-associated macrophages or CCL5 neutralization in vivo leads to the significantly decreased solid tumor infiltration of adoptive T cells in the presence of bacteriotherapy.This combinatorial therapy,consisting of E.coli adjuvant and adoptive T-cell therapy,effectively eradicates early-stage melanoma and inhibits the progression of pancreatic tumors.Notably,this dual strategy also strengthened the distal tumor control capabilities of adoptive T-cell therapy through the induction of in situ tumor vaccination.This dual therapeutic approach involving bacterial therapy targeting the interior of solid tumors and adoptive T-cell therapy attacking the tumor periphery exhibits potent therapeutic efficacy in achieving the eradication of advanced-stage tumors,including melanoma and hepatocellular carcinoma,by converging attacks from both inside and outside the tumor tissues.
查看更多>>摘要：Neoadjuvant PD-1 inhibitor is promising in cutaneous melanoma but remains unknown in acral melanoma(AM).This phase lb trial study(Clinicaltrials.gov NCT04197882)assessed the efficacy and safety of the combination of neoadjuvant oncolytic virus orienX0l0(ori)and anti-PD-1 toripalimab(tori)for resectable AM.Thirty patients of stage Ⅲ/Ⅳ received neoadjuvant therapy of ori and tori for 12 weeks before surgery,followed by adjuvant treatment with tori for 1 year.Primary endpoints were radiographic and pathological response rates,with secondary endpoints of 1-and 2-year recurrence-free survival(RFS)rates,event-free survival(EFS)rates,and safety.Twenty-seven completed surgery and tori adjuvant treatment and median follow-up was 35.7 months.Radiographic and pathological response rates were 36.7％and 77.8％,with complete response rates of 3.3％and 14.8％,1-and 2-year RFS rates of 85.2％and 81.5％,and 1-and 2-year EFS rates of 83％and 73％,respectively.Adverse events occurred in all patients,mainly grade 1-2.There was no correlation between PET/CT evaluation and pathological response or progression-free survival/overall survival.Patients with pathological response showed tumor beds with high tertiary lymphoid structures(TLSs)and tumor-infiltrating lymphocytes(TILs).Cytokines and chemokines analysis showed the combination therapy significantly increases the secretion of proinflammatory cytokines and chemokines in both responders and non-responders.Therefore,neoadjuvant ori and tori demonstrated promising antitumor activity with high response rates and high 2-year RFS/EFS for AM with acceptable tolerability.
查看更多>>摘要：Advanced pancreatic ductal adenocarcinoma(PDAC)has a dismal prognosis.Immunotherapy alone offers limited efficacy,but it is still unknown whether its combination with chemotherapy could offer synergistic anti-tumor effects.This phase Ⅰb/Ⅱ study evaluated the safety and efficacy of combining toripalimab with the gemcitabine plus nab-paclitaxel(GnP)regimen as first-line treatment for locally advanced or metastatic PDAC and explored predictive biomarkers(ChiCTR2000032293).The primary endpoints were safety and overall survival(OS).The secondary outcomes were objective response rate(ORR),disease control rate(DCR),and progression-free survival(PFS).Immune-related biomarkers including programmed death-ligand 1(PD-L1)expression,genetic status,cytokine levels,and spatial features of the tumor immune microenviroment(TIME)were investigated.Neither serious treatment-related adverse events nor grade 4 immune-related adverse events were reported.Among the 72 patients,the median OS was 8.9 months,12-month OS rate was 31.9％,with median PFS of 5.6 months,ORR of 33.3％,and DCR of 90.3％.Higher PD-L1 expression,without liver metastases were associated with higher ORR,however these factors could not effectively distinguish responders and non-responders.Importantly,dendritic cells-T helper cells-cytotoxic T lymphocytes(DC-Th-CTL)enriched immune niche and their spatial interactions were dominant predictors of response based on TIME analysis using a cyclic multiplex tissue staining assay,with an area under the curve value of 0.8.Overall,GnP plus toripalimab exhibited good safety and differentiated efficacy in selected population,and the spatial interactions of DC-Th-CTL represent promising predictors to efficacy of immunochemotherapy in locally advanced or metastatic PDAC.
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