title: Enhancement of adoptive T cell transfer with single low dose pretreatment of doxorubicin or paclitaxel in mice.
abstract: Ex vivo expansion of CD8+ T-cells has been a hindrance for the success of adoptive T cell transfer in clinic. Currently, preconditioning with chemotherapy is used to modulate the patient immunity before ACT, however, the tumor microenvironment beneficial for transferring T cells may also be damaged. Here preconditioning with single low dose of doxorubicin or paclitaxel combined with fewer CD8+ T-cells was investigated to verify whether the same therapeutic efficacy of ACT could be achieved. An E.G7/OT1 animal model that involved adoptive transfer of OVA-specific CD8+ T-cells transduced with a granzyme B promoter-driven firefly luciferase and tomato fluorescent fusion reporter gene was used to evaluate this strategy. The result showed that CD8+ T-cells were activated and sustained longer in mice pretreated with one low-dose Dox or Tax. Enhanced therapeutic efficacy was found in Dox or Tax combined with 2x106 CD8+ T-cells and achieved the same level of tumor growth inhibition as that of 5x106 CD8+ T-cells group. Notably, reduced numbers of Tregs and myeloid derived suppressor cells were shown in combination groups. By contrast, the number of tumor-infiltrating cytotoxic T lymphocytes and IL-12 were increased. The NF-κB activity and immunosuppressive factors such as TGF-β, IDO, CCL2, VEGF, CCL22, COX-2 and IL-10 were suppressed. This study demonstrates that preconditioning with single low dose Dox or Tax and combined with two fifth of the original CD8+ T-cells could improve the tumor microenvironment via suppression of NF-κB and its related immunosuppressors, and activate more CD8+ T-cells which also stay longer.
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.|Department of Medical Imaging, Taipei Medical University Hospital, Taipei, Taiwan.|Translational Imaging Research Center, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Fei-Ting
authors.initials: FT
authors.lastname: Hsu
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.|Department of Radiation Oncology, Chang Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Tzu-Chun
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hui-Yen
authors.initials: HY
authors.lastname: Chuang
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Chang
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.|Biophotonics and Molecular Imaging Research Center (BMIRC), National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jeng-Jong
authors.initials: JJ
authors.lastname: Hwang
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D017930:Genes, Reporter; D053804:Granzymes / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019169:Jurkat Cells; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D019139:Tumor Escape; D059016:Tumor Microenvironment
chemical_list: D007166:Immunosuppressive Agents; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D004317:Doxorubicin; D049409:Luciferases, Firefly; D053804:Granzymes; D017239:Paclitaxel
keywords: Immune response; Immunity; Immunology and Microbiology Section; NF-κB; adoptive T cell transfer; bioluminescent imaging; doxorubicin; paclitaxel