An Oncolytic Adenovirus Targeting Transforming Growth Factor β Inhibits Protumorigenic Signals and Produces Immune Activation: A Novel Approach to Enhance Anti-PD-1 and Anti-CTLA-4 Therapy
| Autor: | Yuefeng Yang, Feng-Jun Xiao, Kathy A. Mangold, Yuan Ji, Megan E. Sullivan, Jinnan Li, Hao Wang, Xiaoyan Zhang, Prem Seth, Yitan Zhu, Xuejie Wu, Kamalakar Gulukota, Weidong Xu, Bellur S. Prabhakar, Lisheng Wang, Donald L. Helseth, Edward Wang, Hua Wang, Karen L. Kaul, Di Peng |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Oncolytic adenovirus
medicine.medical_treatment Genetic Vectors Programmed Cell Death 1 Receptor Virus Replication Adenoviridae Immunomodulation Mice 03 medical and health sciences Antineoplastic Agents Immunological 0302 clinical medicine T-Lymphocyte Subsets Transduction Genetic Transforming Growth Factor beta Cell Line Tumor Neoplasms Genetics medicine Animals Humans CTLA-4 Antigen Telomerase reverse transcriptase Molecular Biology Research Articles 030304 developmental biology Oncolytic Virotherapy 0303 health sciences Mammary tumor biology Chemistry Gene Transfer Techniques Immunity Immunotherapy Combined Modality Therapy Xenograft Model Antitumor Assays Granzyme B Disease Models Animal Oncolytic Viruses Perforin 030220 oncology & carcinogenesis Cancer research biology.protein Cytokines Molecular Medicine CD8 Signal Transduction Transforming growth factor |
| Zdroj: | Hum Gene Ther |
| ISSN: | 1557-7422 1043-0342 |
| Popis: | In an effort to develop a new therapy for cancer and to improve antiprogrammed death inhibitor-1 (anti-PD-1) and anticytotoxic T lymphocyte-associated protein (anti-CTLA-4) responses, we have created a telomerase reverse transcriptase promoter-regulated oncolytic adenovirus rAd.sT containing a soluble transforming growth factor receptor II fused with human IgG Fc fragment (sTGFβRIIFc) gene. Infection of breast and renal tumor cells with rAd.sT produced sTGFβRIIFc protein with dose-dependent cytotoxicity. In immunocompetent mouse 4T1 breast tumor model, intratumoral delivery of rAd.sT inhibited both tumor growth and lung metastases. rAd.sT downregulated the expression of several transforming growth factor β (TGFβ) target genes involved in tumor growth and metastases, inhibited Th2 cytokine expression, and induced Th1 cytokines and chemokines, and granzyme B and perforin expression. rAd.sT treatment also increased the percentage of CD8(+) T lymphocytes, promoted the generation of CD4(+) T memory cells, reduced regulatory T lymphocytes (Tregs), and reduced bone marrow-derived suppressor cells. Importantly, rAd.sT treatment increased the percentage of CD4(+) T lymphocytes, and promoted differentiation and maturation of antigen-presenting dendritic cells in the spleen. In the immunocompetent mouse Renca renal tumor model, similar therapeutic effects and immune activation results were observed. In the 4T1 mammary tumor model, rAd.sT improved the inhibition of tumor growth and lung and liver metastases by anti-PD-1 and anti-CTLA-4 antibodies. Analysis of the human breast and kidney tumors showed that a significant number of tumor tissues expressed high levels of TGFβ and TGFβ-inducible genes. Therefore, rAd.sT could be a potential enhancer of anti-PD-1 and anti-CTLA-4 therapy for treating breast and kidney cancers. |
| Databáze: | OpenAIRE |
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