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CTLA-4 Blockade Enhances Antitumor Immunity of Intratumoral Injection of Immature Dendritic Cells into Irradiated Tumor in a Mouse Colon Cancer Model

Son, Cheol-Hun*,†; Bae, Jae-Ho; Shin, Dong-Yeok*; Lee, Hong-Rae*; Choi, Yoo-Jin*; Jo, Wol-Soon*; Ho Jung, Min; Kang, Chi-Dug; Yang, Kwangmo*; Park, You-Soo*

doi: 10.1097/CJI.0000000000000007
Basic Studies

Dendritic cells (DCs)-based cancer immunotherapy has been used various strategies to inhibit immune suppressive mechanisms. CD25 antibodies and cyclophosphamide are well-studied immunomodulators through inhibition of regulatory T cells (Treg) and a blockade the immune-checkpoint molecule, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) was recently targeted for immunomodulation. We used anti-CTLA-4 antibody, which is known to induce effective antitumor immunity by facilitating tumor-specific T-cell activation and suppressing Treg cells, as useful immunomodulator to provide a potentiating effect in the intratumoral injection of immature DCs (iDCs) into the irradiated tumor (IR/iDC). Ionizing radiation (IR) was applied at a dose of 10 Gy to the tumor on the right thigh of mice. Then, iDCs were intratumorally injected into the irradiated tumor. Anti-CTLA-4 antibody (100 µg/mouse) was administered intraperitoneally to mice on the same day with every iDCs injection. The growth of distant tumors was inhibited by IR/iDC and this effect was significantly augmented by combination treatment of anti-CTLA-4 antibody. Furthermore, the survival rate of tumor-bearing mice improved more by the combination treatment of anti-CTLA-4 antibody and IR/iDC compared with other groups. It was related to the increased tumor-specific interferon-γ-secreting T cells and CTL activity. Therefore, our results demonstrated that immunomodulator such as anti-CTLA-4 antibody enhances antitumor immunity of intratumoral injection of iDCs into irradiated tumor and suggested a new strategy to get more clinical benefits for cancer treatment.

*Department of Research Center, Dongnam Institute of Radiological and Medical Sciences

Department of Microbiology, Dong-A University College of Medicine, Busan

Department of Biochemistry, Pusan National University School of Medicine, Yangsan, Korea

Reprints: You-Soo Park, Department of Research Center, Dongnam Institute of Radiological and Medical Sciences, Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan 619-953, Korea (e-mail: biotek01@hanmail.net).

Received May 7, 2013

Accepted October 13, 2013

© 2014 by Lippincott Williams & Wilkins