Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300020, China.
Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Mol Ther. 2018 Mar 7;26(3):695-707. doi: 10.1016/j.ymthe.2018.01.007. Epub 2018 Jan 17.
Growing evidence links the aggressiveness of non-Hodgkin's lymphoma, especially the activated B cell-like type diffuse large B cell lymphomas (ABC-DLBCLs) to Toll-like receptor 9 (TLR9)/MyD88 and STAT3 transcription factor signaling. Here, we describe a dual-function molecule consisting of a clinically relevant TLR9 agonist (CpG7909) and a STAT3 inhibitor in the form of a high-affinity decoy oligodeoxynucleotide (dODN). The CpG-STAT3dODN blocked STAT3 DNA binding and activity, thus reducing expression of downstream target genes, such as MYC and BCL2L1, in human and mouse lymphoma cells. We further demonstrated that injections (i.v.) of CpG-STAT3dODN inhibited growth of human OCI-Ly3 lymphoma in immunodeficient mice. Moreover, systemic CpG-STAT3dODN administration induced complete regression of the syngeneic A20 lymphoma, resulting in long-term survival of immunocompetent mice. Both TLR9 stimulation and concurrent STAT3 inhibition were critical for immune-mediated therapeutic effects, since neither CpG7909 alone nor CpG7909 co-injected with unconjugated STAT3dODN extended mouse survival. The CpG-STAT3dODN induced expression of genes critical to antigen-processing/presentation and Th1 cell activation while suppressing survival signaling. These effects resulted in the generation of lymphoma cell-specific CD8/CD4-dependent T cell immunity protecting mice from tumor rechallenge. Our results suggest that CpG-STAT3dODN as a systemic/local monotherapy or in combination with PD1 blockade can provide an opportunity for treating patients with B cell NHL.
越来越多的证据表明，非霍奇金淋巴瘤的侵袭性，特别是激活 B 细胞样弥漫大 B 细胞淋巴瘤（ABC-DLBCL）与 Toll 样受体 9（TLR9）/MyD88 和 STAT3 转录因子信号有关。在这里，我们描述了一种由临床相关 TLR9 激动剂（CpG7909）和 STAT3 抑制剂组成的双功能分子，其形式为高亲和力的诱饵寡脱氧核苷酸（dODN）。CpG-STAT3dODN 阻断 STAT3 DNA 结合和活性，从而降低人类和小鼠淋巴瘤细胞中下游靶基因（如 MYC 和 BCL2L1）的表达。我们进一步证明，CpG-STAT3dODN 的注射（iv）抑制了免疫缺陷小鼠中人类 OCI-Ly3 淋巴瘤的生长。此外，系统给予 CpG-STAT3dODN 可诱导同源 A20 淋巴瘤的完全消退，从而导致免疫功能正常的小鼠长期存活。TLR9 刺激和同时抑制 STAT3 对于免疫介导的治疗效果至关重要，因为单独使用 CpG7909 或与未缀合的 STAT3dODN 共同注射均不能延长小鼠的存活时间。CpG-STAT3dODN 诱导了对抗原加工/呈递和 Th1 细胞激活至关重要的基因的表达，同时抑制了存活信号。这些作用导致了淋巴瘤细胞特异性 CD8/CD4 依赖性 T 细胞免疫的产生，从而保护小鼠免受肿瘤再挑战。我们的结果表明，CpG-STAT3dODN 作为全身/局部单一疗法或与 PD1 阻断联合使用，为治疗 B 细胞 NHL 患者提供了机会。
