Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy.
Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy.
复制标题
用于神经胶质瘤免疫治疗的包裹在合成蛋白纳米颗粒中的辅助CXCR 4-CXCL 12信号传导抑制剂的全身递送。
DOI：
10.1021/acsnano.1c07492
复制
发表时间：
2022-06-28
期刊：
影响因子：
17.1
通讯作者：
Castro, Maria G.
中科院分区：
文献类型：
--
作者：
Alghamri, Mahmoud S.;Banerjee, Kaushik;Mujeeb, Anzar A.;Mauser, Ava;Taher, Ayman;Thalla, Rohit;McClellan, Brandon L.;Varela, Maria L.;Stamatovic, Svetlana M.;Martinez-Revollar, Gabriela;V. Andjelkovic, Anuska;V. Gregory, Jason;Kadiyala, Padma;Calinescu, Alexandra;Jimenez, Jennifer A.;Apfelbaum, April A.;Lawlor, Elizabeth R.;Carney, Stephen;Comba, Andrea;Faisal, Syed Mohd;Barissi, Marcus;Edwards, Marta B.;Appelman, Henry;Sun, Yilun;Gan, Jingyao;Ackermann, Rose;Schwendeman, Anna;Candolfi, Marianela;Olin, Michael R.;Lahann, Joerg;Lowenstein, Pedro R.;Castro, Maria G.
关键词：
胶质母细胞瘤（GBM）是一种侵袭性原发性脑癌; 5年生存率约为5%。阻碍GBM治疗功效的挑战包括：（i）肿瘤异质性，（ii）治疗抗性，（iii）免疫抑制性肿瘤微环境（TME）和（iv）血脑屏障（BBB）。C-X-C基序趋化因子配体-12/ C-X-C基序趋化因子受体-4（CXCL 12/CXCR 4）信号通路在GBM中被激活，并与肿瘤进展相关。CXCR 4拮抗剂（AMD 3100）是一种有吸引力的抗GBM治疗靶点，但其不良的药代动力学特性和生物利用度阻碍了其临床应用。因此，我们开发了包被有转胞吞肽iRGD（AMD 3100-SPNP）的合成蛋白纳米颗粒（SPNP），以通过全身递送靶向GBM中的CXCL 2/CXCR 4通路。我们发现，AMD 3100-SPNP在体外的三种小鼠和人GBM细胞培养物中以及在体内的GBM小鼠模型中阻断CXCL 12/CXCR 4信号传导。这导致（i）GBM增殖的抑制，（ii）CXCR 4+单核细胞骨髓源性抑制细胞（M-MDSC）向TME中的浸润减少，（iii）BBB完整性的恢复，和（iv）免疫原性细胞死亡（ICD）的诱导，使肿瘤对放射疗法敏感，并导致抗GBM免疫。此外，我们表明，将AMD 3100-SPNP与辐射组合导致长期存活;在对侧半球用第二GBM再激发后，约60%的GBM荷瘤小鼠保持无肿瘤。这是由于持续的抗GBM免疫记忆反应，在没有额外治疗的情况下防止了肿瘤复发。鉴于有效的ICD诱导和重编程的肿瘤微环境，这种SPNP介导的策略具有显著的临床翻译适用性。用AMD 3100缀合的纳米颗粒（SPNP）阻断CXCR 4信号传导途径后靶向胶质母细胞瘤（GBM）的免疫机制。(1)放射治疗诱导胶质瘤细胞死亡，随后释放损伤相关分子模式（DAMP）释放。树突状细胞（DC）被DAMP激活并迁移到局部淋巴结，在那里它们引发细胞毒性T淋巴细胞免疫应答。肿瘤特异性细胞毒性T细胞浸润肿瘤并靶向神经胶质瘤细胞。(2)胶质瘤细胞表达CXCR 4及其配体CXCL 12。CXCL 12诱导胶质瘤细胞增殖，（3）CXCL 12介导表达CXCR 4的MDSC从骨髓中动员，其浸润肿瘤，并抑制肿瘤特异性细胞毒性T细胞活性。用SPNPs AMD 3100-SPNPs联合放射治疗胶质瘤GEMM。AMD 3100-SPNP抑制CXCR 4和CXCL 12之间的相互作用，因此（4）抑制神经胶质瘤细胞增殖和（5）减少表达CXCR 4的骨髓MDSC在骨髓中的动员，（6）导致MDSC肿瘤浸润减少和增强肿瘤特异性细胞毒性T细胞应答。
Glioblastoma (GBM) is an aggressive primary brain cancer; with a 5-year survival of ~5%. Challenges that hamper GBM therapeutic efficacy include: (i) tumor heterogeneity, (ii) treatment resistance, (iii) immunosuppressive tumor microenvironment (TME) and (iv) the blood-brain barrier (BBB). The C-X-C Motif Chemokine Ligand-12/ C-X-C Motif Chemokine Receptor-4 (CXCL12/CXCR4) signaling pathway is activated in GBM and is associated with tumor progression. Although the CXCR4 antagonist (AMD3100) has been proposed as an attractive anti-GBM therapeutic target, it’s poor pharmacokinetic properties, and unfavorable bioavailability have hampered its clinical implementation. Thus, we developed synthetic protein nanoparticles (SPNPs) coated with the transcytotic peptide iRGD (AMD3100-SPNPs) to target the CXCL2/CXCR4 pathway in GBM via systemic delivery. We showed that AMD3100-SPNPs block CXCL12/CXCR4 signaling in three mouse and human GBM cell cultures in vitro and in a GBM mouse model in vivo. This results in (i) inhibition of GBM proliferation, (ii) reduced infiltration of CXCR4+ monocytic myeloid derived suppressor cells (M-MDSCs) into the TME, (iii) restoration of BBB integrity, and (iv) induction of immunogenic cell death (ICD), sensitizing the tumor to radiotherapy, and leading to anti-GBM immunity. Additionally, we showed that combining AMD3100-SPNPs with radiation led to long term survival; with ~60% of GBM tumor bearing mice remaining tumor free, after rechallenging with a second GBM in the contralateral hemisphere. This was due to a sustained anti-GBM immunological memory response that prevented tumor recurrence without additional treatment. In view of the potent ICD induction and reprogrammed tumor microenvironment, this SPNP-mediated strategy has a significant clinical translation applicability. Immunological mechanism targeting Glioblastoma (GBM) upon blocking CXCR4 signaling pathway with AMD3100-conjugated nanoparticles (SPNPs). (1) Radiotherapy induces glioma cell death, followed by release of Damage-associated molecular patterns (DAMPs) release. Dendritic cells (DC) are activated by DAMPs and migrate to the regional lymph node where they prime cytotoxic T lymphocyte immune response. Tumor-specific cytotoxic T cells infiltrate the tumor and target glioma cells. (2) Glioma cells express CXCR4, as well its ligand CXCL12. CXCL12 induces glioma cell proliferation and, (3) CXCL12 mediates mobilization of CXCR4 expressing MDSC from bone marrow, which infiltrate the tumor, and inhibit tumor-specific cytotoxic T cells activity. GEMM of glioma were treated systemically with SPNPs AMD3100-SPNPs plus radiation. AMD3100-SPNPs inhibit the interaction between CXCR4 and CXCL12, thus (4) inhibiting glioma cell proliferation and (5) reducing mobilization in the bone marrow of CXCR4 expressing myeloid MDSC, (6) leading a reduced MDSC tumor infiltration and enhancing tumor specific cytotoxic T cell response.
登录
查看更多内容
影响因子：
4.7
作者：
Himes BT;Geiger PA;Ayasoufi K;Bhargav AG;Brown DA;Parney IF
通讯作者：
Parney IF
DOI：
10.1158/1078-0432.ccr-15-2888
发表时间：
2017-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Calinescu AA;Yadav VN;Carballo E;Kadiyala P;Tran D;Zamler DB;Doherty R;Srikanth M;Lowenstein PR;Castro MG
通讯作者：
Castro MG
影响因子：
12.4
作者：
Kamran, Neha;Kadiyala, Padma;Castro, Maria G.
通讯作者：
Castro, Maria G.
影响因子：
1.2
作者：
Baker, Gregory J.;Castro, Maria G.;Lowenstein, Pedro R.
通讯作者：
Lowenstein, Pedro R.
影响因子：
5.3
作者：
Guyon A
通讯作者：
Guyon A