Zhang Chunyan, Huang Rui, Ren Lyuzhi, Martincuks Antons, Song JiEun, Kortylewski Marcin, Swiderski Piotr, Forman Stephen J, Yu Hua
Department of Immuno-Oncology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA.
DNA/RNA Synthesis Core Facility, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA.
Mol Ther Nucleic Acids. 2024 Oct 9;35(4):102357. doi: 10.1016/j.omtn.2024.102357. eCollection 2024 Dec 10.
Immune checkpoint blockade (ICB) therapy has significantly benefited patients with several types of solid tumors and some lymphomas. However, many of the treated patients do not have a durable clinical response. It has been demonstrated that rescuing exhausted CD8 T cells is required for ICB-mediated antitumor effects. We recently developed an immunostimulatory strategy based on silencing STAT3 while stimulating immune responses by CpG, a ligand for Toll-like receptor 9 (TLR9). The CpG-small interfering RNA (siRNA) conjugates efficiently enter immune cells, silencing STAT3 and activating innate immunity to enhance T cell-mediated antitumor immune responses. In the present study, we demonstrate that blocking STAT3 through locally delivered CpG- siRNA enhances the efficacies of the systemic PD-1 and CTLA4 blockade against mouse A20 B cell lymphoma. In addition, locally delivered CpG- siRNA combined with systemic administration of PD-1 antibody significantly augmented both local and systemic antitumor effects against mouse B16 melanoma tumors, with enhanced tumor-associated T cell activation. Furthermore, locally delivered CpG- siRNA enhanced CD8 T cell tumor infiltration and antitumor activity in a xenograft tumor model. Overall, our studies in both B cell lymphoma and melanoma mouse models demonstrate the potential of combinatory immunotherapy with CpG- siRNA and checkpoint inhibitors as a therapeutic strategy for B cell lymphoma and melanoma.
免疫检查点阻断（ICB）疗法已使多种实体瘤患者和一些淋巴瘤患者显著受益。然而，许多接受治疗的患者并没有持久的临床反应。已有研究表明，挽救耗竭的CD8 T细胞是ICB介导的抗肿瘤效应所必需的。我们最近开发了一种免疫刺激策略，即通过沉默信号转导和转录激活因子3（STAT3），同时利用Toll样受体9（TLR9）的配体CpG刺激免疫反应。CpG小干扰RNA（siRNA）偶联物能有效进入免疫细胞，沉默STAT3并激活先天免疫，以增强T细胞介导的抗肿瘤免疫反应。在本研究中，我们证明通过局部递送CpG-siRNA阻断STAT3可增强全身PD-1和CTLA4阻断对小鼠A20 B细胞淋巴瘤的疗效。此外，局部递送CpG-siRNA与全身给予PD-1抗体相结合，可显著增强对小鼠B16黑色素瘤肿瘤的局部和全身抗肿瘤作用，并增强肿瘤相关T细胞的激活。此外，在异种移植肿瘤模型中，局部递送CpG-siRNA可增强CD8 T细胞的肿瘤浸润和抗肿瘤活性。总体而言，我们在B细胞淋巴瘤和黑色素瘤小鼠模型中的研究表明，CpG-siRNA与检查点抑制剂联合免疫疗法作为B细胞淋巴瘤和黑色素瘤的治疗策略具有潜力。
