CD8 T cell–specific induction of NKG2D receptor by doxorubicin plus interleukin-12 and its contribution to CD8 T cell accumulation in tumorsReport as inadecuate




CD8 T cell–specific induction of NKG2D receptor by doxorubicin plus interleukin-12 and its contribution to CD8 T cell accumulation in tumors - Download this document for free, or read online. Document in PDF available to download.

Molecular Cancer

, 13:34

First Online: 24 February 2014Received: 09 August 2013Accepted: 03 February 2014DOI: 10.1186-1476-4598-13-34

Cite this article as: Hu, J., Zhu, S., Xia, X. et al. Mol Cancer 2014 13: 34. doi:10.1186-1476-4598-13-34

Abstract

BackgroundIncreased infiltration of CD8T cells into tumors has a positive impact on survival. Our previous study showed that doxorubicin Dox plus interleukin-12 IL-12 boosted the accumulation of CD8T cells in tumors and had a greater antitumor effect than did either agent alone. The purpose of this study was to determine the impact of NKG2D expression on CD8T cell infiltration and antitumor efficacy.

MethodsTumor-bearing mice were administered Dox, IL-12 plasmid DNA, or both via intraperitoneal injection or intramuscular electroporation. The induction of NKG2D on CD8T cells and other lymphocytes was analyzed via flow cytometry, and NKG2D-positive CD8T cell–specific localization in tumors was determined by using immunofluorescence staining in various types of immune cell–depleted mice.

ResultsThe combination of Dox plus IL-12 specifically increased expression of NKG2D in CD8T cells but not in other types of immune cells, including NK cells, which naturally express NKG2D. This induced NKG2D expression in CD8T cells was associated with increased accumulation of CD8T cells in murine tumors. Administration of NKG2D-blocking antibody or CD8T cell–depletion antibody abrogated the NKG2DCD8T cell detection in tumors, whereas administration of NK cell–depletion antibody had no effect. Increased NKG2D expression in CD8T cells was associated with increased antitumor efficacy in vivo.

ConclusionWe conclude that Dox plus IL-12 induces NKG2D in CD8T cells in vivo and boosts NKG2DCD8T-dependent antitumor immune surveillance. This discovery reveals a novel mechanism for how chemoimmunotherapy synergistically promotes T cell–mediated antitumor immune surveillance.

KeywordsInterleukin-12 Doxorubicin Tumor-infiltrating lymphocytes NKG2DCD8T cells AbbreviationsNKNatural killer

DoxDoxorubicin

IL-12Interleukin-12

pCtrlControl plasmid DNA

pIL-12IL-12 plasmid DNA

NKG2DNatural killer group 2, member D

PBSPhosphate-buffered saline solution

FITCFluorescein isothiocyanate

siRNASmall-interfering RNA

KOKnockout

IFNInterferon.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-13-34 contains supplementary material, which is available to authorized users.

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Author: Jiemiao Hu - Shiguo Zhu - Xueqing Xia - Liangfang Zhang - Eugenie S Kleinerman - Shulin Li

Source: https://link.springer.com/



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