Immunostimulatory nanoparticle incorporating two immune agonists for the treatment of pancreatic tumors.
Immunostimulatory nanoparticle incorporating two immune agonists for the treatment of pancreatic tumors.
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含有两种免疫激动剂的免疫刺激纳米粒，用于治疗胰腺肿瘤。
DOI：
10.1016/j.jconrel.2020.11.014
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发表时间：
2021-02-10
期刊：
影响因子：
--
通讯作者：
Karathanasis E
中科院分区：
文献类型：
--
作者：
Lorkowski ME;Atukorale PU;Bielecki PA;Tong KH;Covarrubias G;Zhang Y;Loutrianakis G;Moon TJ;Santulli AR;Becicka WM;Karathanasis E
胰腺导管腺癌（PDAC）是一种高度恶性的疾病，即使手术切除和积极的化疗也会产生令人沮丧的结果。免疫疗法是一种很有前途的替代传统治疗方法，具有诱导T细胞介导的肿瘤细胞杀伤和预防疾病复发的能力。到目前为止，免疫治疗方法在PDAC中取得的成功有限，这是由于免疫原性差和极度免疫抑制的肿瘤微环境，其中富含功能失调和免疫抑制的抗原提呈细胞（APCs）。我们开发了一种高效的免疫刺激纳米颗粒（immune - np）来激活和扩大肿瘤中的APC，并诱导局部分泌干扰素β (IFNβ)，干扰素β是一种促炎细胞因子，在APC募集中起主要作用。免疫np的有效性源于其两种协同免疫调节剂的双重负载，包括干扰素基因刺激剂（STING）途径的激动剂和toll样受体4 （TLR4）途径的激动剂。我们发现，通过调整免疫np中两种激动剂的比例，可以调整双激动剂货物的功能协同作用，从而导致与任何单一激动剂免疫np变体相比，IFNβ产量增加（11倍）。利用PDAC的原位小鼠Panc02模型，我们发现全身给药可以使免疫nps沉积到肿瘤的血管周围区域，这与富含apc的肿瘤区域相吻合，导致apc主要摄取免疫nps。免疫nps被肿瘤中相当一部分树突状细胞有效吸收（>56%）。这导致apc的显著扩增，导致整个胰腺肿瘤的树突状细胞和淋巴细胞浸润比未治疗的动物增加11.5倍。
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease, where even surgical resection and aggressive chemotherapy produce dismal outcomes. Immunotherapy is a promising alternative to conventional treatments, possessing the ability to elicit T cell-mediated killing of tumor cells and prevent disease recurrence. Immunotherapeutic approaches thus far have seen limited success in PDAC due to a poorly immunogenic and exceedingly immunosuppressive tumor microenvironment, which is enriched with dysfunctional and immunosuppressed antigen-presenting cells (APCs). We developed a highly potent immunostimulatory nanoparticle (immuno-NP) to activate and expand APCs in the tumor and induce local secretion of interferon β (IFNβ), which is a pro-inflammatory cytokine that plays a major role in APC recruitment. The effectiveness of the immuno-NP stems from its dual cargo of two synergistic immune modulators consisting of an agonist of the stimulator of interferon genes (STING) pathway and an agonist of the Toll-like receptor 4 (TLR4) pathway. We show the functional synergy of the dual-agonist cargo can be tweaked by adjusting the ratio of the two agonists loaded in the immuno-NP, leading to an increase in IFNβ production (11-fold) compared to any single agonist immuno-NP variant. Using the orthotopic murine Panc02 model of PDAC, we show that systemic administration allowed immuno-NPs to deposit into the perivascular regions of the tumor, which coincided with the APC-rich tumor areas leading to predominant uptake of immuno-NPs by APCs. The immuno-NPs were effectively taken up by a significant portion of dendritic cells in the tumor (>56%). This led to a significant expansion of APCs, resulting in an 11.5-fold increase of dendritic cells and infiltration of lymphocytes throughout the pancreatic tumor compared to untreated animals.
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DOI：
10.1084/jem.20101159
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fuertes MB;Kacha AK;Kline J;Woo SR;Kranz DM;Murphy KM;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
DOI：
10.1073/pnas.1512832112
发表时间：
2015-12-15
影响因子：
11.1
作者：
Demaria, Olivier;De Gassart, Aude;Gilliet, Michel
通讯作者：
Gilliet, Michel
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
PD-1和PD-L1抑制剂作为癌症免疫疗法的一种形式的开发：对注册试验和未来考虑的全面综述。
影响因子：
10.9
作者：
Gong J;Chehrazi-Raffle A;Reddi S;Salgia R
通讯作者：
Salgia R