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Silencing IDO in dendritic cells: A novel approach to enhance cancer immunotherapy in a murine breast cancer model
Author(s) -
Zheng Xiufen,
Koropatnick James,
Chen Di,
Velenosi Thomas,
Ling Hong,
Zhang Xusheng,
Jiang Nan,
Navarro Benjamin,
Ichim Thomas E.,
Urquhart Bradley,
Min Weiping
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27710
Subject(s) - immunotherapy , gene silencing , medicine , foxp3 , cancer research , dendritic cell , cancer , cancer immunotherapy , antigen , breast cancer , immunology , cd8 , ctl* , cancer vaccine , immune system , biology , gene , biochemistry
Cancer immunotherapeutic agents (vaccines) in the form of antigen‐loaded dendritic cells (DCs) reached an important milestone with the recent approval of Provenge, the first DC vaccine for treatment of prostate cancer. Although this heralds a new era of tumor immunotherapy, it also highlights the compelling need to optimize such DC‐based therapies as they are increasingly tested and used to treat human patients. In this study we sought to augment and enhance the antitumor activity of a DC‐based vaccine using siRNA to silence expression of immunosuppressive enzyme indoleamine 2,3‐dioxygenase (IDO) in DCs. We report here that DCs loaded with tumor antigens, but with siRNA‐silenced IDO expression, were introduced into 4T1 breast tumor‐bearing mice, the treatment: ( i ) lengthened the time required for tumor onset, ( ii ) decreased tumor size compared to tumors grown for equal lengths of time in mice treated with antigen‐loaded DCs without IDO silencing and ( iii ) reduced CD4 + and CD8 + T cell apoptosis. Furthermore, immunization with IDO‐silenced DCs enhanced tumor antigen‐specific T cell proliferation and CTL activity, and decreased numbers of CD4 + CD25 + Foxp3 + T reg . This study provides evidence to support silencing of immunosuppressive genes (IDO) as an effective strategy to enhance the efficacy of DC‐based cancer immunotherapeutic.