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
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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":15.8000,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adj9366","citationCount":"0","resultStr":"{\"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. 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引用次数: 0
摘要
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。
Nanoparticle delivery of innate immune agonists combined with senescence-inducing agents promotes T cell control of pancreatic cancer
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.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.