CTLA-4 blockade enhances antitumor immunity of intratumoral injection of immature dendritic cells into irradiated tumor in a mouse colon cancer model

• Published in: Journal of immunotherapy (1997) Vol. 37; no. 1; p. 1
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States 01.01.2014
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Cell Line, Tumor; Colonic Neoplasms - immunology; Colonic Neoplasms - mortality; Colonic Neoplasms - radiotherapy; Colonic Neoplasms - therapy; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 Antigen - immunology; Dendritic Cells - immunology; Dendritic Cells - transplantation; Disease Models, Animal; Immunotherapy, Adoptive; Interferon-gamma - biosynthesis; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Male; Mice; T-Lymphocytes, Cytotoxic - immunology; Th1 Cells - drug effects; Th1 Cells - immunology
• ISSN: 1537-4513
• DOI: 10.1097/CJI.0000000000000007

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.