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}
Pub Date : 2024-08-21DOI: 10.1126/scitranslmed.adl4222
Zhongcheng Mei, May A. Khalil, Yizhan Guo, Dongge Li, Anirban Banerjee, Mojtaba Taheri, Christina M. Kratzmeier, Kelly Chen, Christine L. Lau, Irina G. Luzina, Sergei P. Atamas, Sivaveera Kandasamy, Daniel Kreisel, Andrew E. Gelman, Elizabeth A. Jacobsen, Alexander Sasha Krupnick
Respiratory failure occurs more frequently after thoracic surgery than abdominal surgery. Although the etiology for this complication is frequently attributed to underlying lung disease present in patients undergoing thoracic surgery, this notion is often unfounded because many patients with normal preoperative pulmonary function often require prolonged oxygen supplementation even after minimal resection of lung tissue. Using a murine model of pulmonary resection and peripheral blood samples from patients undergoing resection of the lung or abdominal organs, we demonstrated that lung surgery initiates a proinflammatory loop that results in damage to the remaining lung tissue, noncardiogenic pulmonary edema, hypoxia, and even death. Specifically, we demonstrated that resection of murine lung tissue increased concentrations of the homeostatic cytokine interleukin-7, which led to local and systemic activation of type 2 innate lymphoid cells. This process activated lung-resident eosinophils and facilitated stress-induced eosinophil maturation in the bone marrow in a granulocyte-macrophage colony-stimulating factor–dependent manner, resulting in systemic eosinophilia in both mice and humans. Up-regulation of inducible nitric oxide synthase in lung-resident eosinophils led to tissue nitrosylation, pulmonary edema, hypoxia, and, at times, death. Disrupting this activation cascade at any stage ameliorated deleterious outcomes and improved survival after lung resection in the mouse model. Our data suggest that repurposing US Food and Drug Administration–approved eosinophil-targeting strategies may potentially offer a therapeutic intervention to improve outcomes for patients who require lung resection for benign or malignant etiology.
{"title":"Stress-induced eosinophil activation contributes to postoperative morbidity and mortality after lung resection","authors":"Zhongcheng Mei, May A. Khalil, Yizhan Guo, Dongge Li, Anirban Banerjee, Mojtaba Taheri, Christina M. Kratzmeier, Kelly Chen, Christine L. Lau, Irina G. Luzina, Sergei P. Atamas, Sivaveera Kandasamy, Daniel Kreisel, Andrew E. Gelman, Elizabeth A. Jacobsen, Alexander Sasha Krupnick","doi":"10.1126/scitranslmed.adl4222","DOIUrl":"10.1126/scitranslmed.adl4222","url":null,"abstract":"<div >Respiratory failure occurs more frequently after thoracic surgery than abdominal surgery. Although the etiology for this complication is frequently attributed to underlying lung disease present in patients undergoing thoracic surgery, this notion is often unfounded because many patients with normal preoperative pulmonary function often require prolonged oxygen supplementation even after minimal resection of lung tissue. Using a murine model of pulmonary resection and peripheral blood samples from patients undergoing resection of the lung or abdominal organs, we demonstrated that lung surgery initiates a proinflammatory loop that results in damage to the remaining lung tissue, noncardiogenic pulmonary edema, hypoxia, and even death. Specifically, we demonstrated that resection of murine lung tissue increased concentrations of the homeostatic cytokine interleukin-7, which led to local and systemic activation of type 2 innate lymphoid cells. This process activated lung-resident eosinophils and facilitated stress-induced eosinophil maturation in the bone marrow in a granulocyte-macrophage colony-stimulating factor–dependent manner, resulting in systemic eosinophilia in both mice and humans. Up-regulation of inducible nitric oxide synthase in lung-resident eosinophils led to tissue nitrosylation, pulmonary edema, hypoxia, and, at times, death. Disrupting this activation cascade at any stage ameliorated deleterious outcomes and improved survival after lung resection in the mouse model. Our data suggest that repurposing US Food and Drug Administration–approved eosinophil-targeting strategies may potentially offer a therapeutic intervention to improve outcomes for patients who require lung resection for benign or malignant etiology.</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":"142018453","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.adn0904
Zhen Lu, Ioannis Verginadis, Motofumi Kumazoe, Gerardo M. Castillo, Yao Yao, Rebecca E. Guerra, Sandra Bicher, Menghao You, George McClung, Rong Qiu, Zebin Xiao, Zhen Miao, Subin S. George, Daniel P. Beiting, Takashi Nojiri, Yasutake Tanaka, Yoshinori Fujimura, Hiroaki Onda, Yui Hatakeyama, Akiko Nishimoto-Ashfield, Katrina Bykova, Wei Guo, Yi Fan, Nikolay M. Buynov, J. Alan Diehl, Ben Z. Stanger, Hirofumi Tachibana, Terence P. Gade, Ellen Puré, Constantinos Koumenis, Elijah M. Bolotin, Serge Y. Fuchs
Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.
{"title":"Modified C-type natriuretic peptide normalizes tumor vasculature, reinvigorates antitumor immunity, and improves solid tumor therapies","authors":"Zhen Lu, Ioannis Verginadis, Motofumi Kumazoe, Gerardo M. Castillo, Yao Yao, Rebecca E. Guerra, Sandra Bicher, Menghao You, George McClung, Rong Qiu, Zebin Xiao, Zhen Miao, Subin S. George, Daniel P. Beiting, Takashi Nojiri, Yasutake Tanaka, Yoshinori Fujimura, Hiroaki Onda, Yui Hatakeyama, Akiko Nishimoto-Ashfield, Katrina Bykova, Wei Guo, Yi Fan, Nikolay M. Buynov, J. Alan Diehl, Ben Z. Stanger, Hirofumi Tachibana, Terence P. Gade, Ellen Puré, Constantinos Koumenis, Elijah M. Bolotin, Serge Y. Fuchs","doi":"10.1126/scitranslmed.adn0904","DOIUrl":"10.1126/scitranslmed.adn0904","url":null,"abstract":"<div >Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents.</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":"142018451","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 : 2024-08-14DOI: 10.1126/scitranslmed.adi6626
Xue Dong, Yinting Song, Yuming Liu, Xuejing Kou, Tianjing Yang, Samuel X. Shi, Kai He, Yiming Li, Ziqi Li, Xueming Yao, Ju Guo, Bohao Cui, Ziru Wu, Yi Lei, Mei Du, Mei Chen, Heping Xu, Qiang Liu, Fu-Dong Shi, Xiaohong Wang, Hua Yan
Neovascular age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Although it is known that nvAMD is associated with focal inflammation, understanding of the precise immune components governing this process remains limited. Here, we identified natural killer (NK) cells as a prominent lymphocyte population infiltrating the perivascular space of choroidal neovascularization (CNV) lesions in patients with nvAMD and in mouse models. Olink proteomic analysis and single-cell RNA sequencing combined with knockout studies demonstrated the involvement of C-C chemokine receptor 5 (CCR5) in NK cell recruitment and extravasation at the CNV sites of mice. Depletion of NK cells or inhibition of activating receptor NK group 2, member D (NKG2D) inhibited the formation of neutrophil extracellular traps, increased vascular leakage, and exacerbated pathological angiogenesis, indicating that NK cells restrain pathogenesis in this mouse model. Age is the strongest risk factor for AMD, and we show that NK cells from aged human donors exhibited a less cytotoxic phenotype. NK cells from old mice exhibited compromised protective effects in the CNV mouse model. In addition, interleukin-2 complex–mediated expansion of NK cells improved CNV formation in mice. Collectively, our study highlights NK cells as a potential therapeutic target for patients with nvAMD.
新生血管性老年黄斑变性（nvAMD）是老年人失明的主要原因。尽管人们知道新生血管性老年黄斑变性与局灶性炎症有关，但对支配这一过程的精确免疫成分的了解仍然有限。在这里，我们发现自然杀伤（NK）细胞是渗入nvAMD患者和小鼠模型脉络膜新生血管（CNV）病变血管周围空间的主要淋巴细胞群。Olink蛋白组分析和单细胞RNA测序结合基因敲除研究证明，C-C趋化因子受体5（CCR5）参与了小鼠CNV部位的NK细胞招募和外渗。消耗NK细胞或抑制活化受体NK 2组D成员（NKG2D）可抑制中性粒细胞胞外捕获物的形成、增加血管渗漏并加剧病理性血管生成，这表明NK细胞抑制了该小鼠模型的发病机制。年龄是导致老年性视网膜病变的最大风险因素，而我们的研究表明，来自高龄人类供体的 NK 细胞表现出较低的细胞毒性表型。在 CNV 小鼠模型中，来自高龄小鼠的 NK 细胞表现出的保护作用也大打折扣。此外，白介素-2 复合物介导的 NK 细胞扩增改善了小鼠 CNV 的形成。总之，我们的研究强调了 NK 细胞是 nvAMD 患者的潜在治疗靶点。
{"title":"Natural killer cells promote neutrophil extracellular traps and restrain macular degeneration in mice","authors":"Xue Dong, Yinting Song, Yuming Liu, Xuejing Kou, Tianjing Yang, Samuel X. Shi, Kai He, Yiming Li, Ziqi Li, Xueming Yao, Ju Guo, Bohao Cui, Ziru Wu, Yi Lei, Mei Du, Mei Chen, Heping Xu, Qiang Liu, Fu-Dong Shi, Xiaohong Wang, Hua Yan","doi":"10.1126/scitranslmed.adi6626","DOIUrl":"10.1126/scitranslmed.adi6626","url":null,"abstract":"<div >Neovascular age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Although it is known that nvAMD is associated with focal inflammation, understanding of the precise immune components governing this process remains limited. Here, we identified natural killer (NK) cells as a prominent lymphocyte population infiltrating the perivascular space of choroidal neovascularization (CNV) lesions in patients with nvAMD and in mouse models. Olink proteomic analysis and single-cell RNA sequencing combined with knockout studies demonstrated the involvement of C-C chemokine receptor 5 (CCR5) in NK cell recruitment and extravasation at the CNV sites of mice. Depletion of NK cells or inhibition of activating receptor NK group 2, member D (NKG2D) inhibited the formation of neutrophil extracellular traps, increased vascular leakage, and exacerbated pathological angiogenesis, indicating that NK cells restrain pathogenesis in this mouse model. Age is the strongest risk factor for AMD, and we show that NK cells from aged human donors exhibited a less cytotoxic phenotype. NK cells from old mice exhibited compromised protective effects in the CNV mouse model. In addition, interleukin-2 complex–mediated expansion of NK cells improved CNV formation in mice. Collectively, our study highlights NK cells as a potential therapeutic target for patients with nvAMD.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983131","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 : 2024-08-14DOI: 10.1126/scitranslmed.adl0715
Hui Chen, Stéphanie Moriceau, Adrien Joseph, Francois Mailliet, Sijing Li, Virginie Tolle, Philibert Duriez, Roland Dardennes, Sylvère Durand, Vincent Carbonnier, Gautier Stoll, Allan Sauvat, Sylvie Lachkar, Fanny Aprahamian, Carolina Alves Costa Silva, Hui Pan, Léa Montégut, Gerasimos Anagnostopoulos, Flavia Lambertucci, Omar Motiño, Uxía Nogueira-Recalde, Mélanie Bourgin, Misha Mao, Yuhong Pan, Alexandra Cerone, Erwan Boedec, Zelia L. Gouveia, Federica Marmorino, Chiara Cremolini, Lisa Derosa, Laurence Zitvogel, Oliver Kepp, Carlos López-Otín, Maria Chiara Maiuri, Franck Perez, Philip Gorwood, Nicolas Ramoz, Franck Oury, Isabelle Martins, Guido Kroemer
Extracellular acyl-coenzyme A binding protein [ACBP encoded by diazepam binding inhibitor (DBI)] is a phylogenetically ancient appetite stimulator that is secreted in a nonconventional, autophagy-dependent fashion. Here, we show that low ACBP/DBI plasma concentrations are associated with poor prognosis in patients with anorexia nervosa, a frequent and often intractable eating disorder. In mice, anorexia induced by chronic restraint stress (CRS) is accompanied by a reduction in circulating ACBP/DBI concentrations. We engineered a chemical-genetic system for the secretion of ACBP/DBI through a biotin-activatable, autophagy-independent pathway. In transgenic mice expressing this system in hepatocytes, biotin-induced elevations in plasma ACBP/DBI concentrations prevented anorexia induced by CRS or chemotherapeutic agents including cisplatin, doxorubicin, and paclitaxel. ACBP/DBI reversed the CRS or cisplatin-induced increase in plasma lipocalin-2 concentrations and the hypothalamic activation of anorexigenic melanocortin 4 receptors, for which lipocalin-2 is an agonist. Daily intravenous injections of recombinant ACBP/DBI protein or subcutaneous implantation of osmotic pumps releasing recombinant ACBP/DBI mimicked the orexigenic effects of the chemical-genetic system. In conclusion, the supplementation of extracellular and peripheral ACBP/DBI might constitute a viable strategy for treating anorexia.
{"title":"Acyl-CoA binding protein for the experimental treatment of anorexia","authors":"Hui Chen, Stéphanie Moriceau, Adrien Joseph, Francois Mailliet, Sijing Li, Virginie Tolle, Philibert Duriez, Roland Dardennes, Sylvère Durand, Vincent Carbonnier, Gautier Stoll, Allan Sauvat, Sylvie Lachkar, Fanny Aprahamian, Carolina Alves Costa Silva, Hui Pan, Léa Montégut, Gerasimos Anagnostopoulos, Flavia Lambertucci, Omar Motiño, Uxía Nogueira-Recalde, Mélanie Bourgin, Misha Mao, Yuhong Pan, Alexandra Cerone, Erwan Boedec, Zelia L. Gouveia, Federica Marmorino, Chiara Cremolini, Lisa Derosa, Laurence Zitvogel, Oliver Kepp, Carlos López-Otín, Maria Chiara Maiuri, Franck Perez, Philip Gorwood, Nicolas Ramoz, Franck Oury, Isabelle Martins, Guido Kroemer","doi":"10.1126/scitranslmed.adl0715","DOIUrl":"10.1126/scitranslmed.adl0715","url":null,"abstract":"<div >Extracellular acyl-coenzyme A binding protein [ACBP encoded by diazepam binding inhibitor (DBI)] is a phylogenetically ancient appetite stimulator that is secreted in a nonconventional, autophagy-dependent fashion. Here, we show that low ACBP/DBI plasma concentrations are associated with poor prognosis in patients with anorexia nervosa, a frequent and often intractable eating disorder. In mice, anorexia induced by chronic restraint stress (CRS) is accompanied by a reduction in circulating ACBP/DBI concentrations. We engineered a chemical-genetic system for the secretion of ACBP/DBI through a biotin-activatable, autophagy-independent pathway. In transgenic mice expressing this system in hepatocytes, biotin-induced elevations in plasma ACBP/DBI concentrations prevented anorexia induced by CRS or chemotherapeutic agents including cisplatin, doxorubicin, and paclitaxel. ACBP/DBI reversed the CRS or cisplatin-induced increase in plasma lipocalin-2 concentrations and the hypothalamic activation of anorexigenic melanocortin 4 receptors, for which lipocalin-2 is an agonist. Daily intravenous injections of recombinant ACBP/DBI protein or subcutaneous implantation of osmotic pumps releasing recombinant ACBP/DBI mimicked the orexigenic effects of the chemical-genetic system. In conclusion, the supplementation of extracellular and peripheral ACBP/DBI might constitute a viable strategy for treating anorexia.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adl0715","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983126","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}
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