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

Fei Ting Hsu, Tzu Chun Chen, Hui Yen Chuang, Ya Fang Chang, Jeng Jong Hwang

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

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 2×106 CD8+ T-cells and achieved the same level of tumor growth inhibition as that of 5×106 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-kB 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-kB and its related immunosuppressors, and activate more CD8+ T-cells which also stay longer.

Original languageEnglish
Pages (from-to)44134-44150
Number of pages17
JournalOncotarget
Volume6
Issue number42
DOIs
Publication statusPublished - 2015
Externally publishedYes

Keywords

  • Adoptive T cell transfer
  • Bioluminescent imaging
  • Doxorubicin
  • Immune response
  • Immunity
  • Immunology and microbiology section
  • Immunomodulation
  • NF-kB
  • Paclitaxel

ASJC Scopus subject areas

  • Oncology

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