Enhancement of adoptive T cell transfer with single low dose pretreatment of doxorubicin or paclitaxel in mice

// Fei-Ting Hsu 1,2,3,* , Tzu-Chun Chen 1,4,* , Hui-Yen Chuang 1 , Ya-Fang Chang 1 and Jeng-Jong Hwang 1,5 1 Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan 2 Department of Medical Imaging, Taipei Medical University Hospital, Taipei, Taiwan 3 Translational Imaging Research Center, College of Medicine, Taipei Medical University, Taipei, Taiwan 4 Department of Radiation Oncology, Chang Gung Memorial Hospital, Linkou, Taiwan 5 Biophotonics and Molecular Imaging Research Center (BMIRC), National Yang-Ming University, Taipei, Taiwan * These authors have contributed equally in this work Correspondence to: Jeng-Jong Hwang, email: // Keywords : adoptive T cell transfer, bioluminescent imaging, doxorubicin, NF-κB, paclitaxel, Immunology and Microbiology Section, Immune response, Immunity Received : August 30, 2015 Accepted : November 25, 2015 Published : December 16, 2015 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 2x10 6 CD8 + T-cells and achieved the same level of tumor growth inhibition as that of 5x10 6 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.