Nanoparticle delivery of innate immune agonists combines with senescence-inducing agents to mediate T cell control of pancreatic cancer.
Nanoparticle delivery of innate immune agonists combines with senescence-inducing agents to mediate T cell control of pancreatic cancer.
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先天免疫激动剂的纳米粒子递送与衰老诱导剂相结合，介导 T 细胞对胰腺癌的控制。
DOI：
10.1101/2023.09.18.558307
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Fitzgerald,Katherine
中科院分区：
文献类型：
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作者：
Chibaya,Loretah;Lusi,ChristinaF;DeMarco,KellyD;Kane,GriffinI;Brassil,MeghanL;Parikh,ChaitanyaN;Murphy,KatherineC;Li,Junhui;Naylor,TianaE;Cerrutti,Julia;Peura,Jessica;Pitarresi,JasonR;Zhu,LihuaJulie;Fitzgerald,Katherine
胰腺导管腺癌已迅速上升为癌症相关死亡的第三大原因。这在一定程度上是由于其纤维化的肿瘤微环境(TME)，导致血管形成和免疫渗透不良，以及随后的化疗和免疫治疗失败。在这里，我们研究了一种创新的免疫治疗方法，通过脂基纳米粒(NPs)共包裹局部递送STING和TLR4天然免疫激动剂与诱导衰老的RAS靶向治疗相结合，可以通过衰老相关的分泌表型重塑免疫抑制PDAC TME。用这些方案治疗移植的和自体的PDAC小鼠模型，可以增强PDAC TME中多种细胞对NPs的摄取，诱导I型干扰素和其他促炎信号，增加肿瘤细胞和抗原提呈细胞的抗原提呈，并随后激活固有和获得性免疫反应。这种双管齐下的方法在临床前PDAC模型中产生了有效的T细胞驱动和I型干扰素依赖的肿瘤退化和长期生存。STIN和TLR4介导的I型干扰素信号也与人PDAC中NK和CD8+T细胞免疫增强有关。因此，将局部免疫激动剂的传递与全身肿瘤靶向治疗相结合，可以协同协调先天性和获得性免疫攻击，以克服免疫抑制，并激活针对PDAC的持久抗肿瘤T细胞反应。
Pancreatic ductal adenocarcinoma has quickly risen to become the 3rd leading cause of cancer-related death. This is in part due to its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here we investigated an innovative immunotherapy approach combining local delivery of STING and TLR4 innate immune agonists via lipid-based nanoparticles (NPs) co-encapsulation with senescence-inducing RAS-targeted therapies that 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 pro-inflammatory signaling, 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-dependent tumor regressions and long-term survival in preclinical PDAC models. STING and TLR4-mediated Type I interferon signaling were also associated with enhanced NK and CD8+ T cell immunity in human PDAC. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can synergize to orchestrate a coordinated innate and adaptive immune assault to overcome immune suppression and activate durable anti-tumor T cell responses against PDAC.