Cargo-free immunomodulatory nanoparticles combined with anti-PD-1 antibody for treating metastatic breast cancer.
Cargo-free immunomodulatory nanoparticles combined with anti-PD-1 antibody for treating metastatic breast cancer.
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无货物免疫调节纳米颗粒联合抗PD - 1抗体用于治疗转移性乳腺癌
DOI：
10.1016/j.biomaterials.2021.120666
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发表时间：
2021-03
期刊：
影响因子：
14
通讯作者：
Shea LD
中科院分区：
文献类型：
--
作者：
Zhang Y;Hughes KR;Raghani RM;Ma J;Orbach S;Jeruss JS;Shea LD
免疫抑制性先天免疫细胞，如髓源性抑制细胞（MDSCs）、ly6c高单核细胞和肿瘤相关巨噬细胞（tam）在肿瘤中的存在可以抑制效应T细胞和NK细胞的功能。使用抗pd -1抗体的免疫检查点阻断旨在克服免疫抑制环境，但只有一小部分患者有反应。在此，我们在转移性三阴性乳腺癌4T1小鼠模型中验证了一种假设，即静脉注射无载物PLG纳米颗粒可以将循环免疫细胞从肿瘤微环境中转移出来，从而增强抗pd -1免疫治疗的疗效。体外研究表明，这些纳米颗粒被先天免疫细胞摄取后，可使MCP-1的表达降低5倍，使TNF-α的表达增加2倍以上。静脉注射颗粒导致MDSCs和单核细胞内化，在肝、肺、脾和原发肿瘤中检测到颗粒。纳米颗粒递送降低了循环系统和肺部MDSCs的丰度，后者是主要转移部位。与抗pd -1抗体联合使用，纳米颗粒显著减缓了肿瘤的生长，并带来了生存益处。GSEA基因表达分析显示，炎性髓细胞通路在肺中下调，在脾和肿瘤中上调。在原发肿瘤中也观察到外源性凋亡通路的上调。总之，这些结果表明，无载物PLG纳米颗粒可以重编程免疫细胞反应，改变体内肿瘤微环境，以克服髓系细胞的局部免疫抑制，增强抗pd -1治疗的疗效。
The presence of immunosuppressive innate immune cells such as myeloid derived suppressor cells (MDSCs), Ly6C-high monocytes, and tumor-associated macrophages (TAMs) at a tumor can inhibit effector T cell and NK cell function. Immune checkpoint blockade using anti-PD-1 antibody aims to overcome the immune suppressive environment, yet only a fraction of patients responds. Herein, we test the hypothesis that cargo-free PLG nanoparticles administered intravenously can divert circulating immune cells from the tumor microenvironment to enhance the efficacy of anti-PD-1 immunotherapy in the 4T1 mouse model of metastatic triple-negative breast cancer. In vitro studies demonstrate that these nanoparticles decrease the expression of MCP-1 by 5-fold and increase the expression of TNF-α by more than 2-fold upon uptake by innate immune cells. Intravenous administration of particles results in internalization by MDSCs and monocytes, with particles detected in the liver, lung, spleen, and primary tumor. Nanoparticle delivery decreased the abundance of MDSCs in circulation and in the lung, the latter being the primary metastatic site. Combined with anti-PD-1 antibody, nanoparticles significantly slowed tumor growth and resulted in a survival benefit. Gene expression analysis by GSEA indicated inflammatory myeloid cell pathways were downregulated in the lung and upregulated in the spleen and tumor. Upregulation of extrinsic apoptotic pathways was also observed in the primary tumor. Collectively, these results demonstrate that cargo-free PLG nanoparticles can reprogram immune cell responses and alter the tumor microenvironment in vivo to overcome the local immune suppression attributed to myeloid cells and enhance the efficacy of anti-PD-1 therapy.
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影响因子：
10.1
作者：
Gabrilovich DI
通讯作者：
Gabrilovich DI
DOI：
10.4049/jimmunol.1000901
发表时间：
2010-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lechner MG;Liebertz DJ;Epstein AL
通讯作者：
Epstein AL
影响因子：
17.1
作者：
Hunter Z;McCarthy DP;Yap WT;Harp CT;Getts DR;Shea LD;Miller SD
通讯作者：
Miller SD
影响因子：
6.6
作者：
Angell, Trevor E.;Lechner, Melissa G.;Epstein, Alan L.
通讯作者：
Epstein, Alan L.
影响因子：
16.6
作者：
Bronte V;Brandau S;Chen SH;Colombo MP;Frey AB;Greten TF;Mandruzzato S;Murray PJ;Ochoa A;Ostrand-Rosenberg S;Rodriguez PC;Sica A;Umansky V;Vonderheide RH;Gabrilovich DI
通讯作者：
Gabrilovich DI