Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States.
Interdisciplinary Biological Sciences Graduate Program, Northwestern University, Evanston, IL, United States.
Front Immunol. 2020 Jul 8;11:1333. doi: 10.3389/fimmu.2020.01333. eCollection 2020.
Although the strategy of therapeutic vaccination for the treatment of prostate cancer has advanced to and is available in the clinic (Sipuleucel-T), the efficacy of such therapy remains limited. Here, we develop Immunostimulatory Spherical Nucleic Acid (IS-SNA) nanostructures comprised of CpG oligonucleotides as adjuvant and prostate cancer peptide antigens, and evaluate their antitumor efficacy in syngeneic mouse models of prostate cancer. IS-SNAs with the specific structural feature of presenting both antigen and adjuvant CpG on the surface (hybridized model (HM) SNAs) induce stronger cytotoxic T lymphocyte (CTL) mediated antigen-specific killing of target cells than that for IS-SNAs with CpG on the surface and antigen encapsulated within the core (encapsulated model (EM) SNAs). Mechanistically, HM SNAs increase the co-delivery of CpG and antigen to dendritic cells over that for EM SNAs or admixtures of linear CpG and peptide, thereby improving cross-priming of antitumor CD8 T cells. As a result, vaccination with HM SNAs leads to more effective antitumor immune responses in two prostate cancer models. These data demonstrate the importance of the structural positioning of peptide antigens together with adjuvants within IS-SNAs to the efficacy of IS-SNA-based cancer immunotherapy.
虽然治疗性疫苗接种治疗前列腺癌的策略已经发展到并可在临床上应用（Sipuleucel-T），但这种治疗的疗效仍然有限。在这里，我们开发了由 CpG 寡核苷酸作为佐剂和前列腺癌肽抗原组成的免疫刺激球形核酸（IS-SNA）纳米结构，并在前列腺癌的同基因小鼠模型中评估了它们的抗肿瘤疗效。具有表面呈现抗原和佐剂 CpG 的特定结构特征的 IS-SNAs（杂交模型（HM）SNAs）比表面具有 CpG 而抗原包封在核心内的 IS-SNAs（包封模型（EM）SNAs）诱导更强的细胞毒性 T 淋巴细胞（CTL）介导的靶细胞抗原特异性杀伤。从机制上讲，HM SNAs 比 EM SNAs 或线性 CpG 和肽混合物将 CpG 和抗原更有效地共递送至树突状细胞，从而改善抗肿瘤 CD8 T 细胞的交叉呈递。结果，HM SNAs 疫苗接种在两种前列腺癌模型中导致更有效的抗肿瘤免疫反应。这些数据表明，肽抗原与 IS-SNA 内佐剂的结构定位对基于 IS-SNA 的癌症免疫疗法的疗效很重要。
