Diabetic vascular disease is a major complication of diabetes mellitus (DM). Chemokine C-C motif ligand 7 (CCL7) attracts macrophages and monocytes, amplifying inflammatory processes in the vasculature. We hypothesized a causal role for CCL7 in diabetic vasculopathy. CCL7 concentrations were higher in the plasma of patients with type 2 DM, as well as in supernatants from their endothelial progenitor cells (EPCs). High-glucose stimulation increased the secretion of CCL7 from human dermal microvascular endothelial cells (HDMECs) through the c-Fos and c-Jun signaling pathways. CCL7 inhibition using knockdown or neutralization antibody treatment reversed the high glucose–induced impaired tube formation and migration abilities of EPCs, human aortic endothelial cells, human coronary artery endothelial cells, and HDMECs. Administration of recombinant human CCL7 protein impaired tube formation and migration abilities by down-regulating the AKT–endothelial nitric oxide synthase and AKT/nuclear factor erythroid 2–related factor 2/heme oxygenase–1/vascular endothelial growth factor/stromal cell–derived factor–1 pathways and by up-regulating ERK/phosphorylated p65/interleukin-1β/interleukin-6/tumor necrosis factor–α pathways through CC chemokine receptor 3 in endothelial cells. Ccl7 knockout in streptozotocin-treated mice showed improved neovasculogenesis in ischemic limbs and accelerated wound repair, with increased circulating EPCs and capillary density. CCL7 antibody treatment in db/db mice and high-fat diet–induced hyperglycemia mice showed improved neovasculogenesis in ischemic limbs and wound areas, accompanied by up-regulation of angiogenic proteins and down-regulation of inflammatory proteins. Endothelial cell–specific Ccl7-knockout mice showed ameliorated diabetic vasculopathy in streptozotocin-induced DM. This study highlights the potential of CCL7 as a therapeutic target for diabetic vasculopathy.
{"title":"Inhibition of CCL7 improves endothelial dysfunction and vasculopathy in mouse models of diabetes mellitus","authors":"Ting-Ting Chang, You-Zhen Li, Hsiao-Wei Mo, Ching Chen, Liang-Yu Lin, Chia-Chi Chang, Jaw-Wen Chen","doi":"10.1126/scitranslmed.adn1507","DOIUrl":"10.1126/scitranslmed.adn1507","url":null,"abstract":"<div >Diabetic vascular disease is a major complication of diabetes mellitus (DM). Chemokine C-C motif ligand 7 (CCL7) attracts macrophages and monocytes, amplifying inflammatory processes in the vasculature. We hypothesized a causal role for CCL7 in diabetic vasculopathy. CCL7 concentrations were higher in the plasma of patients with type 2 DM, as well as in supernatants from their endothelial progenitor cells (EPCs). High-glucose stimulation increased the secretion of CCL7 from human dermal microvascular endothelial cells (HDMECs) through the c-Fos and c-Jun signaling pathways. CCL7 inhibition using knockdown or neutralization antibody treatment reversed the high glucose–induced impaired tube formation and migration abilities of EPCs, human aortic endothelial cells, human coronary artery endothelial cells, and HDMECs. Administration of recombinant human CCL7 protein impaired tube formation and migration abilities by down-regulating the AKT–endothelial nitric oxide synthase and AKT/nuclear factor erythroid 2–related factor 2/heme oxygenase–1/vascular endothelial growth factor/stromal cell–derived factor–1 pathways and by up-regulating ERK/phosphorylated p65/interleukin-1β/interleukin-6/tumor necrosis factor–α pathways through CC chemokine receptor 3 in endothelial cells. <i>Ccl7</i> knockout in streptozotocin-treated mice showed improved neovasculogenesis in ischemic limbs and accelerated wound repair, with increased circulating EPCs and capillary density. CCL7 antibody treatment in <i>db/db</i> mice and high-fat diet–induced hyperglycemia mice showed improved neovasculogenesis in ischemic limbs and wound areas, accompanied by up-regulation of angiogenic proteins and down-regulation of inflammatory proteins. Endothelial cell–specific <i>Ccl7</i>-knockout mice showed ameliorated diabetic vasculopathy in streptozotocin-induced DM. This study highlights the potential of CCL7 as a therapeutic target for diabetic vasculopathy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1126/scitranslmed.ads3171
{"title":"Erratum for the Research Article “MEK-SHP2 inhibition prevents tibial pseudarthrosis caused by NF1 loss in Schwann cells and skeletal stem/progenitor cells” by S. Perrin et al.","authors":"","doi":"10.1126/scitranslmed.ads3171","DOIUrl":"10.1126/scitranslmed.ads3171","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lung regeneration after fibrosis requires formation of functional new vasculature, which is essential for gas exchange and cellular cross-talk with other lung cells. It remains unknown how the lung vasculature can be regenerated without fibrosis. Here, we tested the role of N6-methyladenosine (m6A) modification of forkhead box protein O1 (Foxo1) mRNA in lung regeneration after pneumonectomy (PNX) in mice, a model for lung regrowth after surgical resection. Endothelial cell (EC)–specific knockout of methyltransferase-like 3 (Mettl3) and Foxo1 caused nonproductive intussusceptive angiogenesis (IA), which impaired regeneration and enhanced fibrosis. This nonproductive IA was characterized by enhanced endothelial proliferation and increased vascular splitting with increased numbers of pillar ECs. Endothelial-selective knockout of Mettl3 in mice stimulated nonproductive IA and up-regulation of profibrotic factors after PNX, promoting regeneration to fibrotic transition. EC-specific mutation of m6A modification sites in the Foxo1 gene in mice revealed that endothelial Mettl3 modified A504 and A2035 sites in the Foxo1 mRNA to maintain pro-regenerative endothelial glycolysis, ensuring productive IA and lung regeneration without fibrosis. Suppression of Mettl3-Foxo1 signaling stimulated a subset of hyperglycolytic and hyperproliferative 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3)+, Ras homolog family member J (Rhoj)+, and platelet-derived growth factor subunit B (Pdgfb)+ ECs in both human and mouse lungs with fibrosis. Inhibiting this Pfkfb3+Rhoj+Pdgfb+ EC subset normalized IA, alleviated fibrosis, and restored regeneration in bleomycin (BLM)–injured mouse lungs. We found that m6A modification of Foxo1 in the mouse vasculature promoted lung regeneration over fibrosis after PNX and BLM injury.
{"title":"Inhibiting endothelial Rhoj blocks profibrotic vascular intussusception and angiocrine factors to sustain lung regeneration","authors":"Jie Ma, Liyin Zhang, Xu Zhang, Lanlan Zhang, Hua Zhang, Yulei Zhu, Xingming Huang, Ting Zhang, Xiangdong Tang, Yuan Wang, Lu Chen, Qiang Pu, Liming Yang, Zhongwei Cao, Bi-Sen Ding","doi":"10.1126/scitranslmed.ado5266","DOIUrl":"10.1126/scitranslmed.ado5266","url":null,"abstract":"<div >Lung regeneration after fibrosis requires formation of functional new vasculature, which is essential for gas exchange and cellular cross-talk with other lung cells. It remains unknown how the lung vasculature can be regenerated without fibrosis. Here, we tested the role of N6-methyladenosine (m6A) modification of <i>forkhead box protein O1</i> (<i>Foxo1</i>) mRNA in lung regeneration after pneumonectomy (PNX) in mice, a model for lung regrowth after surgical resection. Endothelial cell (EC)–specific knockout of <i>methyltransferase-like 3</i> (<i>Mettl3</i>) and <i>Foxo1</i> caused nonproductive intussusceptive angiogenesis (IA), which impaired regeneration and enhanced fibrosis. This nonproductive IA was characterized by enhanced endothelial proliferation and increased vascular splitting with increased numbers of pillar ECs. Endothelial-selective knockout of <i>Mettl3</i> in mice stimulated nonproductive IA and up-regulation of profibrotic factors after PNX, promoting regeneration to fibrotic transition. EC-specific mutation of m6A modification sites in the <i>Foxo1</i> gene in mice revealed that endothelial <i>Mettl3</i> modified A504 and A2035 sites in the <i>Foxo1</i> mRNA to maintain pro-regenerative endothelial glycolysis, ensuring productive IA and lung regeneration without fibrosis. Suppression of <i>Mettl3-Foxo1</i> signaling stimulated a subset of hyperglycolytic and hyperproliferative <i>6-phosphofructo-2-kinase/fructose-2</i>,<i>6-biphosphatase 3</i> (<i>Pfkfb3</i>)<sup>+</sup>, <i>Ras homolog family member J</i> (<i>Rhoj</i>)<sup>+</sup>, and <i>platelet-derived growth factor subunit B</i> (<i>Pdgfb</i>)<sup>+</sup> ECs in both human and mouse lungs with fibrosis. Inhibiting this <i>Pfkfb3</i><sup>+</sup><i>Rhoj</i><sup>+</sup><i>Pdgfb</i><sup>+</sup> EC subset normalized IA, alleviated fibrosis, and restored regeneration in bleomycin (BLM)–injured mouse lungs. We found that m6A modification of <i>Foxo1</i> in the mouse vasculature promoted lung regeneration over fibrosis after PNX and BLM injury.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1126/scitranslmed.adk7399
Ying Liu, Feng Wang, Dongxue Peng, Dan Zhang, Luping Liu, Jun Wei, Jian Yuan, Luyao Zhao, Huimin Jiang, Tingting Zhang, Yunxuan Li, Chenxi Zhao, Shuhua He, Jie Wu, Yechao Yan, Peitao Zhang, Chunyi Guo, Jiaming Zhang, Xia Li, Huan Gao, Ke Li
CD8+ T cell activation leads to the rapid proliferation and differentiation of effector T cells (Teffs), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8+ Teffs, the mechanisms that regulate CD8+ T cell glucose uptake in the low-glucose and acidic tumor microenvironment (TME) remain poorly understood. Here, we report that the abundance of the glucose transporter GLUT10 is increased during CD8+ T cell activation and antitumor immunity. Specifically, GLUT10 deficiency inhibited glucose uptake, glycolysis, and antitumor efficiency of tumor-infiltrating CD8+ T cells. Supplementation with glucose alone was insufficient to rescue the antitumor function and glucose uptake of CD8+ T cells in the TME. By analyzing tumor environmental metabolites, we found that high concentrations of lactic acid reduced the glucose uptake, activation, and antitumor effects of CD8+ T cells by directly binding to GLUT10’s intracellular motif. Disrupting the interaction of lactic acid and GLUT10 by the mimic peptide PG10.3 facilitated CD8+ T cell glucose utilization, proliferation, and antitumor functions. The combination of PG10.3 and GLUT1 inhibition or anti–programmed cell death 1 antibody treatment showed synergistic antitumor effects. Together, our data indicate that GLUT10 is selectively required for glucose uptake of CD8+ T cells and identify that TME accumulated lactic acid inhibits CD8+ T cell effector function by directly binding to GLUT10 and reducing its glucose transport capacity. Last, our study suggests disrupting lactate-GLUT10 binding as a promising therapeutic strategy to enhance CD8+ T cell–mediated antitumor effects.
CD8+ T细胞活化会导致效应T细胞（Teffs）快速增殖和分化，从而介导抗肿瘤免疫。虽然有氧糖酵解在 CD8+ Teffs 中优先被激活，但在低糖和酸性肿瘤微环境（TME）中调控 CD8+ T 细胞葡萄糖摄取的机制仍然鲜为人知。在此，我们报告了葡萄糖转运体 GLUT10 在 CD8+ T 细胞活化和抗肿瘤免疫过程中的丰度增加。具体来说，GLUT10 缺乏会抑制葡萄糖摄取、糖酵解和肿瘤浸润 CD8+ T 细胞的抗肿瘤效率。仅补充葡萄糖不足以挽救TME中CD8+ T细胞的抗肿瘤功能和葡萄糖摄取。通过分析肿瘤环境代谢物，我们发现高浓度乳酸通过直接与 GLUT10 的胞内基团结合，降低了 CD8+ T 细胞的葡萄糖摄取、活化和抗肿瘤作用。通过模拟肽 PG10.3 破坏乳酸与 GLUT10 的相互作用，可促进 CD8+ T 细胞的葡萄糖利用、增殖和抗肿瘤功能。PG10.3 与 GLUT1 抑制剂或抗程序性细胞死亡 1 抗体的联合治疗显示出协同抗肿瘤作用。总之，我们的数据表明，CD8+ T 细胞的葡萄糖摄取选择性地需要 GLUT10，并确定 TME 积累的乳酸通过直接与 GLUT10 结合并降低其葡萄糖转运能力来抑制 CD8+ T 细胞的效应功能。最后，我们的研究表明，破坏乳酸与 GLUT10 的结合是一种很有前景的治疗策略，可增强 CD8+ T 细胞介导的抗肿瘤作用。
{"title":"Activation and antitumor immunity of CD8+ T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid","authors":"Ying Liu, Feng Wang, Dongxue Peng, Dan Zhang, Luping Liu, Jun Wei, Jian Yuan, Luyao Zhao, Huimin Jiang, Tingting Zhang, Yunxuan Li, Chenxi Zhao, Shuhua He, Jie Wu, Yechao Yan, Peitao Zhang, Chunyi Guo, Jiaming Zhang, Xia Li, Huan Gao, Ke Li","doi":"10.1126/scitranslmed.adk7399","DOIUrl":"10.1126/scitranslmed.adk7399","url":null,"abstract":"<div >CD8<sup>+</sup> T cell activation leads to the rapid proliferation and differentiation of effector T cells (T<sub>effs</sub>), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8<sup>+</sup> T<sub>effs</sub>, the mechanisms that regulate CD8<sup>+</sup> T cell glucose uptake in the low-glucose and acidic tumor microenvironment (TME) remain poorly understood. Here, we report that the abundance of the glucose transporter GLUT10 is increased during CD8<sup>+</sup> T cell activation and antitumor immunity. Specifically, GLUT10 deficiency inhibited glucose uptake, glycolysis, and antitumor efficiency of tumor-infiltrating CD8<sup>+</sup> T cells. Supplementation with glucose alone was insufficient to rescue the antitumor function and glucose uptake of CD8<sup>+</sup> T cells in the TME. By analyzing tumor environmental metabolites, we found that high concentrations of lactic acid reduced the glucose uptake, activation, and antitumor effects of CD8<sup>+</sup> T cells by directly binding to GLUT10’s intracellular motif. Disrupting the interaction of lactic acid and GLUT10 by the mimic peptide PG10.3 facilitated CD8<sup>+</sup> T cell glucose utilization, proliferation, and antitumor functions. The combination of PG10.3 and GLUT1 inhibition or anti–programmed cell death 1 antibody treatment showed synergistic antitumor effects. Together, our data indicate that GLUT10 is selectively required for glucose uptake of CD8<sup>+</sup> T cells and identify that TME accumulated lactic acid inhibits CD8<sup>+</sup> T cell effector function by directly binding to GLUT10 and reducing its glucose transport capacity. Last, our study suggests disrupting lactate-GLUT10 binding as a promising therapeutic strategy to enhance CD8<sup>+</sup> T cell–mediated antitumor effects.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1126/scitranslmed.adp1720
Tomokazu S. Sumida, Matthew R. Lincoln, Liang He, Yongjin Park, Mineto Ota, Akiko Oguchi, Raku Son, Alice Yi, Helen A. Stillwell, Greta A. Leissa, Keishi Fujio, Yasuhiro Murakawa, Alexander M. Kulminski, Charles B. Epstein, Bradley E. Bernstein, Manolis Kellis, David A. Hafler
Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4+FOXP3+ regulatory T cells (Tregs) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of Tregs in the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity. We found that up-regulation of a primate-specific short isoform of PR domain zinc finger protein 1 (PRDM1-S) induces expression of serum and glucocorticoid-regulated kinase 1 (SGK1) independent from the evolutionarily conserved long PRDM1, which led to destabilization of forkhead box P3 (FOXP3) and Treg dysfunction. This aberrant PRDM1-S/SGK1 axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in Tregs from individuals with MS revealed enriched activating protein–1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of PRDM1-S expression and Treg dysfunction. Our study uncovers a mechanistic model where the evolutionary emergence of PRDM1-S and epigenetic priming of AP-1/IRF may be key drivers of dysfunctional Tregs in autoimmune diseases.
自身免疫性疾病是青壮年最常见的疾病之一，由遗传和环境因素介导。虽然 CD4+FOXP3+ 调节性 T 细胞（Tregs）在预防自身免疫方面发挥着核心作用，但其功能障碍的分子机制尚不清楚。在这里，我们对自身免疫性疾病多发性硬化症（MS）中的Tregs进行了全面的转录组学和表观基因组学分析，以确定调控人类自身免疫的关键转录程序。我们发现，PR结构域锌指蛋白1（PRDM1-S）的灵长类特异性短异构体上调会诱导血清和糖皮质激素调节激酶1（SGK1）的表达，而不依赖于进化保守的长PRDM1，这导致了叉头盒P3（FOXP3）的不稳定和Treg功能障碍。这种异常的 PRDM1-S/SGK1 轴在其他自身免疫性疾病中也存在。此外，对多发性硬化症患者Tregs的染色质图谱分析表明，活化蛋白-1（AP-1）/干扰素调节因子（IRF）转录因子结合丰富，是PRDM1-S表达和Treg功能障碍的候选上游调节因子。我们的研究揭示了一个机制模型，在该模型中，PRDM1-S的进化出现和AP-1/IRF的表观遗传引物可能是自身免疫性疾病中Tregs功能障碍的关键驱动因素。
{"title":"An autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction","authors":"Tomokazu S. Sumida, Matthew R. Lincoln, Liang He, Yongjin Park, Mineto Ota, Akiko Oguchi, Raku Son, Alice Yi, Helen A. Stillwell, Greta A. Leissa, Keishi Fujio, Yasuhiro Murakawa, Alexander M. Kulminski, Charles B. Epstein, Bradley E. Bernstein, Manolis Kellis, David A. Hafler","doi":"10.1126/scitranslmed.adp1720","DOIUrl":"10.1126/scitranslmed.adp1720","url":null,"abstract":"<div >Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4<sup>+</sup>FOXP3<sup>+</sup> regulatory T cells (T<sub>regs</sub>) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of T<sub>regs</sub> in the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity. We found that up-regulation of a primate-specific short isoform of PR domain zinc finger protein 1 (PRDM1-S) induces expression of serum and glucocorticoid-regulated kinase 1 (SGK1) independent from the evolutionarily conserved long <i>PRDM1</i>, which led to destabilization of forkhead box P3 (FOXP3) and T<sub>reg</sub> dysfunction. This aberrant <i>PRDM1-S/SGK1</i> axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in T<sub>regs</sub> from individuals with MS revealed enriched activating protein–1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of <i>PRDM1-S</i> expression and T<sub>reg</sub> dysfunction. Our study uncovers a mechanistic model where the evolutionary emergence of <i>PRDM1-S</i> and epigenetic priming of AP-1/IRF may be key drivers of dysfunctional T<sub>regs</sub> in autoimmune diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1126/scitranslmed.adj9366
Loretah Chibaya, Kelly D. DeMarco, Christina F. Lusi, Griffin I. Kane, Meghan L. Brassil, Chaitanya N. Parikh, Katherine C. Murphy, Shreya R. Chowdhury, Junhui Li, Boyang Ma, Tiana E. Naylor, Julia Cerrutti, Haruka Mori, Miranda Diaz-Infante, Jessica Peura, Jason R. Pitarresi, Lihua Julie Zhu, Katherine A. Fitzgerald, Prabhani U. Atukorale, Marcus Ruscetti
Pancreatic ductal adenocarcinoma (PDAC) has quickly risen to become the third leading cause of cancer-related death in the United States. This is in part because of its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here, we investigated an immunotherapy approach combining delivery of stimulator of interferon genes (STING) and Toll-like receptor 4 (TLR4) innate immune agonists by lipid-based nanoparticle (NP) coencapsulation with senescence-inducing RAS-targeted therapies, which can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other proinflammatory signaling pathways, increased antigen presentation by tumor cells and antigen-presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell–driven and type I interferon–mediated tumor regression and long-term survival in preclinical PDAC models dependent on both tumor and host STING activation. STING and TLR4-mediated type I interferon signaling was also associated with enhanced natural killer and CD8+ T cell immunity in human PDAC samples. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can orchestrate a coordinated type I interferon–driven innate and adaptive immune response with durable antitumor efficacy against PDAC.
胰腺导管腺癌（PDAC）已迅速跃升为美国癌症相关死亡的第三大原因。这部分是由于其纤维化的肿瘤微环境（TME）导致血管化和免疫浸润不良，进而导致化疗和免疫治疗失败。在这里，我们研究了一种免疫疗法，它通过脂基纳米粒子（NP）包被将干扰素基因刺激因子（STING）和Toll样受体4（TLR4）先天性免疫激动剂与衰老诱导RAS靶向疗法相结合，从而通过衰老相关分泌表型重塑免疫抑制性PDAC TME。用这些疗法治疗移植和自体PDAC小鼠模型会增强PDAC TME中多种类型细胞对NPs的吸收，诱导I型干扰素和其他促炎症信号通路，增加肿瘤细胞和抗原递呈细胞的抗原递呈，继而激活先天性和适应性免疫反应。这种双管齐下的方法在临床前 PDAC 模型中产生了强效的 T 细胞驱动和 I 型干扰素介导的肿瘤消退和长期存活，这取决于肿瘤和宿主 STING 的激活。STING 和 TLR4 介导的 I 型干扰素信号也与人类 PDAC 样本中增强的自然杀伤细胞和 CD8+ T 细胞免疫有关。因此，将局部免疫激动剂给药与全身性肿瘤靶向治疗相结合，可以协调I型干扰素驱动的先天性和适应性免疫反应，对PDAC具有持久的抗肿瘤疗效。
{"title":"Nanoparticle delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer","authors":"Loretah Chibaya, Kelly D. DeMarco, Christina F. Lusi, Griffin I. Kane, Meghan L. Brassil, Chaitanya N. Parikh, Katherine C. Murphy, Shreya R. Chowdhury, Junhui Li, Boyang Ma, Tiana E. Naylor, Julia Cerrutti, Haruka Mori, Miranda Diaz-Infante, Jessica Peura, Jason R. Pitarresi, Lihua Julie Zhu, Katherine A. Fitzgerald, Prabhani U. Atukorale, Marcus Ruscetti","doi":"10.1126/scitranslmed.adj9366","DOIUrl":"10.1126/scitranslmed.adj9366","url":null,"abstract":"<div >Pancreatic ductal adenocarcinoma (PDAC) has quickly risen to become the third leading cause of cancer-related death in the United States. This is in part because of its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here, we investigated an immunotherapy approach combining delivery of stimulator of interferon genes (STING) and Toll-like receptor 4 (TLR4) innate immune agonists by lipid-based nanoparticle (NP) coencapsulation with senescence-inducing RAS-targeted therapies, which can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other proinflammatory signaling pathways, increased antigen presentation by tumor cells and antigen-presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell–driven and type I interferon–mediated tumor regression and long-term survival in preclinical PDAC models dependent on both tumor and host STING activation. STING and TLR4-mediated type I interferon signaling was also associated with enhanced natural killer and CD8<sup>+</sup> T cell immunity in human PDAC samples. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can orchestrate a coordinated type I interferon–driven innate and adaptive immune response with durable antitumor efficacy against PDAC.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adj9366","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1126/scitranslmed.adp2660
Joshua D. Bernstock, Jakob V. E. Gerstl, Pablo A. Valdés, Gregory K. Friedman, E. Antonio Chiocca
Interim results from two phase 1 trials demonstrate progress in the use of chimeric antigen receptor (CAR) T cell therapy for recurrent glioblastoma (GBM).
{"title":"Next-generation CAR T cell therapies for glioblastoma","authors":"Joshua D. Bernstock, Jakob V. E. Gerstl, Pablo A. Valdés, Gregory K. Friedman, E. Antonio Chiocca","doi":"10.1126/scitranslmed.adp2660","DOIUrl":"10.1126/scitranslmed.adp2660","url":null,"abstract":"<div >Interim results from two phase 1 trials demonstrate progress in the use of chimeric antigen receptor (CAR) T cell therapy for recurrent glioblastoma (GBM).</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neuroinflammation plays a key role in exacerbating dopaminergic neuron (DAN) loss in Parkinson’s disease (PD). However, it remains unresolved how to effectively normalize this immune response given the complex interplay between the innate and adaptive immune responses occurring within a scarcely accessible organ like the brain. In this study, we uncovered a consistent correlation between neuroinflammation, brain parenchymal lymphocytes, and DAN loss among several commonly used mouse models of PD generated by a variety of pathological triggers. We validated a viral therapeutic approach for the microglia-specific expression of interleukin 10 (IL-10) to selectively mitigate the excessive inflammatory response. We found that this approach induced a local nigral IL-10 release that alleviated DAN loss in mice overexpressing the human SNCA gene in the substantia nigra. Single-cell transcriptomics revealed that IL-10 induced the emergence of a molecularly distinct microglial cell state, enriched in markers of cell activation with enhanced expression of prophagocytic pathways. IL-10 promoted microglial phagocytotic and clearance activities in vitro and reduced αSYN aggregate burden in the nigral area in mice overexpressing SNCA. Furthermore, IL-10 stimulated the differentiation of CD4+ T lymphocytes into active T regulatory cells and promoted inhibitory characteristics in CD8+ T cells. In summary, our results show that local and microglia-specific IL-10 transduction elicited strong immunomodulation in the nigral tissue with enhanced suppression of lymphocyte toxicity that was associated with DAN survival. These results offer insights into the therapeutic benefits of IL-10 and showcase a promising gene delivery approach that could minimize undesired side effects.
神经炎症在加剧帕金森病（PD）多巴胺能神经元（DAN）丢失方面起着关键作用。然而，鉴于先天性免疫反应和适应性免疫反应之间复杂的相互作用发生在大脑这样一个几乎无法触及的器官中，如何有效地使这种免疫反应正常化仍是一个悬而未决的问题。在这项研究中，我们发现了神经炎症、脑实质淋巴细胞和 DAN 丢失之间的一致相关性，这种相关性存在于几种常用的由各种病理诱因产生的帕金森病小鼠模型中。我们验证了一种病毒治疗方法，即小胶质细胞特异性表达白细胞介素 10（IL-10），以选择性地减轻过度炎症反应。我们发现，这种方法能诱导局部黑质 IL-10 的释放，从而减轻黑质中过表达人类 SNCA 基因的小鼠的 DAN 缺失。单细胞转录组学显示，IL-10诱导了一种分子上截然不同的小胶质细胞状态的出现，这种状态富含细胞活化的标记物，并增强了亲吞噬途径的表达。IL-10在体外促进了小胶质细胞的吞噬和清除活动，并减少了过表达SNCA的小鼠黑质区的αSYN聚集负荷。此外，IL-10 还能刺激 CD4+ T 淋巴细胞分化为活跃的 T 调节细胞，并促进 CD8+ T 细胞的抑制特性。总之，我们的研究结果表明，局部和小胶质细胞特异性 IL-10 转导在黑质组织中引起了强烈的免疫调节，增强了对淋巴细胞毒性的抑制，这与 DAN 的存活有关。这些结果让我们深入了解了IL-10的治疗功效，并展示了一种可将不良副作用降至最低的前景广阔的基因递送方法。
{"title":"Microglia-specific IL-10 gene delivery inhibits neuroinflammation and neurodegeneration in a mouse model of Parkinson’s disease","authors":"Simone Bido, Melania Nannoni, Sharon Muggeo, Diana Gambarè, Giorgia Ruffini, Edoardo Bellini, Laura Passeri, Silvia Iaia, Mirko Luoni, Martino Provinciali, Serena Gea Giannelli, Francesca Giannese, Dejan Lazarevic, Silvia Gregori, Vania Broccoli","doi":"10.1126/scitranslmed.adm8563","DOIUrl":"10.1126/scitranslmed.adm8563","url":null,"abstract":"<div >Neuroinflammation plays a key role in exacerbating dopaminergic neuron (DAN) loss in Parkinson’s disease (PD). However, it remains unresolved how to effectively normalize this immune response given the complex interplay between the innate and adaptive immune responses occurring within a scarcely accessible organ like the brain. In this study, we uncovered a consistent correlation between neuroinflammation, brain parenchymal lymphocytes, and DAN loss among several commonly used mouse models of PD generated by a variety of pathological triggers. We validated a viral therapeutic approach for the microglia-specific expression of interleukin 10 (IL-10) to selectively mitigate the excessive inflammatory response. We found that this approach induced a local nigral IL-10 release that alleviated DAN loss in mice overexpressing the human <i>SNCA </i>gene in the substantia nigra. Single-cell transcriptomics revealed that IL-10 induced the emergence of a molecularly distinct microglial cell state, enriched in markers of cell activation with enhanced expression of prophagocytic pathways. IL-10 promoted microglial phagocytotic and clearance activities in vitro and reduced αSYN aggregate burden in the nigral area in mice overexpressing <i>SNCA</i>. Furthermore, IL-10 stimulated the differentiation of CD4<sup>+</sup> T lymphocytes into active T regulatory cells and promoted inhibitory characteristics in CD8<sup>+</sup> T cells. In summary, our results show that local and microglia-specific <i>IL-10 </i>transduction elicited strong immunomodulation in the nigral tissue with enhanced suppression of lymphocyte toxicity that was associated with DAN survival. These results offer insights into the therapeutic benefits of IL-10 and showcase a promising gene delivery approach that could minimize undesired side effects.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1126/scitranslmed.ado1941
Pritesh Desai, Courtney E. Karl, Baoling Ying, Chieh-Yu Liang, Tamara Garcia-Salum, Ana Carolina Santana, Felipe ten-Caten, Joseph F. Urban Jr., Sayda M. Elbashir, Darin K. Edwards, Susan P. Ribeiro, Larissa B. Thackray, Rafick P. Sekaly, Michael S. Diamond
Although vaccines have reduced the burden of COVID-19, their efficacy in helminth infection–endemic areas is not well characterized. We evaluated the impact of infection by Heligmosomoides polygyrus bakeri (Hpb), a murine intestinal roundworm, on the efficacy of an mRNA vaccine targeting the Wuhan-1 spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in mice. Although immunization generated similar B cell responses in Hpb-infected and uninfected mice, polyfunctional CD4+ and CD8+ T cell responses were markedly reduced in Hpb-infected mice. Hpb-infected and mRNA-vaccinated mice were protected against the ancestral SARS-CoV-2 strain WA1/2020, but control of lung infection was diminished against an Omicron variant compared with animals immunized without Hpb infection. Helminth-mediated suppression of spike protein–specific CD8+ T cell responses occurred independently of signal transducer and activator of transcription 6 (STAT6) signaling, whereas blockade of interleukin-10 (IL-10) rescued vaccine-induced CD8+ T cell responses. Together, these data show that, in mice, intestinal helminth infection impaired vaccine-induced T cell responses through an IL-10 pathway, which compromised protection against antigenically drifted SARS-CoV-2 variants.
{"title":"Intestinal helminth infection impairs vaccine-induced T cell responses and protection against SARS-CoV-2 in mice","authors":"Pritesh Desai, Courtney E. Karl, Baoling Ying, Chieh-Yu Liang, Tamara Garcia-Salum, Ana Carolina Santana, Felipe ten-Caten, Joseph F. Urban Jr., Sayda M. Elbashir, Darin K. Edwards, Susan P. Ribeiro, Larissa B. Thackray, Rafick P. Sekaly, Michael S. Diamond","doi":"10.1126/scitranslmed.ado1941","DOIUrl":"10.1126/scitranslmed.ado1941","url":null,"abstract":"<div >Although vaccines have reduced the burden of COVID-19, their efficacy in helminth infection–endemic areas is not well characterized. We evaluated the impact of infection by <i>Heligmosomoides polygyrus bakeri</i> (Hpb), a murine intestinal roundworm, on the efficacy of an mRNA vaccine targeting the Wuhan-1 spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in mice. Although immunization generated similar B cell responses in Hpb-infected and uninfected mice, polyfunctional CD4<sup>+</sup> and CD8<sup>+</sup> T cell responses were markedly reduced in Hpb-infected mice. Hpb-infected and mRNA-vaccinated mice were protected against the ancestral SARS-CoV-2 strain WA1/2020, but control of lung infection was diminished against an Omicron variant compared with animals immunized without Hpb infection. Helminth-mediated suppression of spike protein–specific CD8<sup>+</sup> T cell responses occurred independently of signal transducer and activator of transcription 6 (STAT6) signaling, whereas blockade of interleukin-10 (IL-10) rescued vaccine-induced CD8<sup>+</sup> T cell responses. Together, these data show that, in mice, intestinal helminth infection impaired vaccine-induced T cell responses through an IL-10 pathway, which compromised protection against antigenically drifted SARS-CoV-2 variants.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Immunological imprinting by ancestral SARS-CoV-2 strains is thought to impede the robust induction of Omicron-specific humoral responses by Omicron-based booster vaccines. Here, we analyzed the specificity and neutralization activity of memory B (Bmem) cells after repeated BA.5 exposure in individuals previously imprinted by ancestral strain–based mRNA vaccines. After a second BA.5 exposure, Bmem cells with BA.5 spike protein–skewed reactivity were promptly elicited, correlating with preexisting antibody titers. Clonal lineage analysis identified BA.5-skewed Bmem cells that had redirected their specificity from the ancestral strain to BA.5 through somatic hypermutations. Moreover, Bmem cells with redirected BA.5 specificity exhibited accelerated development compared with de novo Bmem cells derived from naïve repertoires. This redirected BA.5 specificity demonstrated greater resilience to viral point mutation and adaptation to recent Omicron variants HK.3 and JN.1, months after the second BA.5 exposure, suggesting that existing Bmem cells elicited by older vaccines can redirect their specificity toward newly evolving variants.
{"title":"Repeated Omicron exposures redirect SARS-CoV-2–specific memory B cell evolution toward the latest variants","authors":"Ryutaro Kotaki, Saya Moriyama, Shintaro Oishi, Taishi Onodera, Yu Adachi, Eita Sasaki, Kota Ishino, Miwa Morikawa, Hiroaki Takei, Hidenori Takahashi, Tomohiro Takano, Ayae Nishiyama, Kohei Yumoto, Kazutaka Terahara, Masanori Isogawa, Takayuki Matsumura, Masaharu Shinkai, Yoshimasa Takahashi","doi":"10.1126/scitranslmed.adp9927","DOIUrl":"10.1126/scitranslmed.adp9927","url":null,"abstract":"<div >Immunological imprinting by ancestral SARS-CoV-2 strains is thought to impede the robust induction of Omicron-specific humoral responses by Omicron-based booster vaccines. Here, we analyzed the specificity and neutralization activity of memory B (B<sub>mem</sub>) cells after repeated BA.5 exposure in individuals previously imprinted by ancestral strain–based mRNA vaccines. After a second BA.5 exposure, B<sub>mem</sub> cells with BA.5 spike protein–skewed reactivity were promptly elicited, correlating with preexisting antibody titers. Clonal lineage analysis identified BA.5-skewed B<sub>mem</sub> cells that had redirected their specificity from the ancestral strain to BA.5 through somatic hypermutations. Moreover, B<sub>mem</sub> cells with redirected BA.5 specificity exhibited accelerated development compared with de novo B<sub>mem</sub> cells derived from naïve repertoires. This redirected BA.5 specificity demonstrated greater resilience to viral point mutation and adaptation to recent Omicron variants HK.3 and JN.1, months after the second BA.5 exposure, suggesting that existing B<sub>mem</sub> cells elicited by older vaccines can redirect their specificity toward newly evolving variants.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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