Tumor cell lysate-loaded immunostimulatory spherical nucleic acids as therapeutics for triple-negative breast cancer
Tumor cell lysate-loaded immunostimulatory spherical nucleic acids as therapeutics for triple-negative breast cancer
复制标题
DOI：
10.1073/pnas.2005794117
复制
发表时间：
2020-07-28
影响因子：
11.1
通讯作者：
Mirkin, Chad A.
中科院分区：
文献类型：
--
作者：
Callmann, Cassandra E.;Cole, Lisa E.;Mirkin, Chad A.
高度异质性的癌症，如三阴性乳腺癌（TNBC），仍然是具有挑战性的免疫靶点。在此，我们描述了用于TNBC治疗的免疫脂质体球形核酸（SNA）的合成和评价。SNA包含免疫刺激性寡核苷酸（CpG-1826）作为佐剂并包封衍生自TNBC细胞系的裂解物作为抗原。与裂解物与线性寡核苷酸的简单混合物相比，所得纳米结构（Lys-SNA）在体外和体内增强佐剂和抗原向免疫细胞的共递送，并且在TNBC的Py 230和Py 8119原位同基因小鼠模型中相对于裂解物和CpG-1826的简单混合物（Lys-Mix）减少肿瘤生长。此外，在裂解和掺入SNA（OxLys-SNA）之前氧化TNBC细胞相对于其未氧化的对应物显著增加树突细胞的活化。当在EMT 6小鼠乳腺癌模型中瘤周体内施用时，当与Lys-SNA和氧化裂解物与CpG-1826的简单混合物相比时，OxLys-SNA显著增加细胞毒性CD 8 + T细胞的群体，同时减少肿瘤微环境中髓源性抑制细胞（MDSC）的群体。重要的是，施用OxLys-SNA的动物相对于所有其他治疗组表现出显著的抗肿瘤活性和延长的存活，并且抵抗肿瘤再攻击。总之，这些结果表明，裂解物的加工和包装方式对其免疫原性和治疗效果有着深远的影响。此外，这项工作指出了负载氧化肿瘤细胞裂解物的SNA作为缺乏常见治疗靶点的癌症的有效免疫治疗剂的潜力。
Highly heterogenous cancers, such as triple-negative breast cancer (TNBC), remain challenging immunotherapeutic targets. Herein, we describe the synthesis and evaluation of immunotherapeutic liposomal spherical nucleic acids (SNAs) for TNBC therapy. The SNAs comprise immunostimulatory oligonucleotides (CpG-1826) as adjuvants and encapsulate lysates derived from TNBC cell lines as antigens. The resulting nanostructures (Lys-SNAs) enhance the codelivery of adjuvant and antigen to immune cells when compared to simple mixtures of lysates with linear oligonucleotides both in vitro and in vivo, and reduce tumor growth relative to simple mixtures of lysate and CpG-1826 (Lys-Mix) in both Py230 and Py8119 orthotopic syngeneic mouse models of TNBC. Furthermore, oxidizing TNBC cells prior to lysis and incorporation into SNAs (OxLys-SNAs) significantly increases the activation of dendritic cells relative to their nonoxidized counterparts. When administered peritumorally in vivo in the EMT6 mouse mammary carcinoma model, OxLys-SNAs significantly increase the population of cytotoxic CD8+ T cells and simultaneously decrease the population of myeloid derived suppressor cells (MDSCs) within the tumor micro-environment, when compared with Lys-SNAs and simple mixtures of oxidized lysates with CpG-1826. Importantly, animals administered OxLys-SNAs exhibit significant antitumor activity and prolonged survival relative to all other treatment groups, and resist tumor rechallenge. Together, these results show that the way lysates are processed and packaged has a profound impact on their immunogenicity and therapeutic efficacy. Moreover, this work points toward the potential of oxidized tumor cell lysate-loaded SNAs as a potent class of immunotherapeutics for cancers lacking common therapeutic targets.