B Cell Lymphoma Immunotherapy Using TLR9-Targeted Oligonucleotide STAT3 Inhibitors
| العنوان: | B Cell Lymphoma Immunotherapy Using TLR9-Targeted Oligonucleotide STAT3 Inhibitors |
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| المؤلفون: | Hongwei H. Yin, Yong Liang, Larry W. Kwak, Haejung Won, Marcin Kortylewski, Raju Pillai, Zhuoran Zhang, Piotr Swiderski, Xingli Zhao, Dayson Moreira, Stephen J. Forman, Yu-Lin Su, Zhenyuan Dong, Tomasz Adamus |
| المصدر: | Molecular Therapy |
| بيانات النشر: | Elsevier BV, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Transcription, Genetic, medicine.medical_treatment, Oligonucleotides, STAT3, TLR9, Mice, 0302 clinical medicine, T-Lymphocyte Subsets, immune system diseases, hemic and lymphatic diseases, Drug Discovery, Molecular Targeted Therapy, Receptor, B-cell lymphoma, 3. Good health, Treatment Outcome, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Molecular Medicine, Original Article, Immunotherapy, Cell activation, STAT3 Transcription Factor, Lymphoma, B-Cell, CpG oligonucleotides, lymphoma, Antineoplastic Agents, 03 medical and health sciences, Cell Line, Tumor, Genetics, medicine, Immunologic Factors, Animals, Humans, Molecular Biology, B cell, Pharmacology, business.industry, Gene Expression Profiling, medicine.disease, Xenograft Model Antitumor Assays, Lymphoma, Disease Models, Animal, 030104 developmental biology, Toll-Like Receptor 9, Commentary, Cancer research, business, CD8 |
| الوصف: | 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. Graphical Abstract Zhao et al. describe a synthetic oligonucleotide-based strategy for therapy of disseminated B cell lymphomas. They demonstrate that combination of the TLR9 agonist (CpG) with the STAT3 decoy inhibitor into a single oligodeoxynucleotide conjugate generates two-pronged therapeutic effect by direct and T cell-mediated antitumor effects against B cell lymphoma cells in vivo. |
| تدمد: | 1525-0016 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d3b2fe2c4cc6a8b7fc274cda3ff03acfTest https://doi.org/10.1016/j.ymthe.2018.01.007Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d3b2fe2c4cc6a8b7fc274cda3ff03acf |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15250016 |
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