Cytotoxic T lymphocyte-associated antigen 4 inhibition increases the antitumor activity of adoptive T-cell therapy when carried out with naïve rather than differentiated T cells

Ishikawa,Takeshi; Adachi,Satoko; Okayama,Tetsuya; Kokura,Satoshi; Mizushima,Katsura; Doi,Toshifumi; Matsuyama,Tatsuzo; Sakamoto,Naoyuki; Katada,Kazuhiro; Kamada,Kazuhiro; Uchiyama,Kazuhiko; Handa,Osamu; Takagi,Tomohisa; Naito,Yuji; Itoh,Yoshito; Yoshikawa,Toshikazu

doi:10.3892/or.2015.3815

Cytotoxic T lymphocyte-associated antigen 4 inhibition increases the antitumor activity of adoptive T-cell therapy when carried out with naïve rather than differentiated T cells

Authors:
- Takeshi Ishikawa
- Satoko Adachi
- Tetsuya Okayama
- Satoshi Kokura
- Katsura Mizushima
- Toshifumi Doi
- Tatsuzo Matsuyama
- Naoyuki Sakamoto
- Kazuhiro Katada
- Kazuhiro Kamada
- Kazuhiko Uchiyama
- Osamu Handa
- Tomohisa Takagi
- Yuji Naito
- Yoshito Itoh
- Toshikazu Yoshikawa
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Affiliations: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan, Department of Cancer ImmunoCell Regulation, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
Published online on: February 24, 2015 https://doi.org/10.3892/or.2015.3815
Pages: 2545-2552

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Abstract

Although treatment with an antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) combined with multiple therapeutic interventions has been explored, the effect of combination therapy with CTLA-4 inhibition and adoptive T-cell therapy has not been determined. In the present study, our aim was to determine whether CTLA-4 inhibition, combined with adoptive transfer of T cells at different stages of differentiation, exhibits synergistic antitumor effects in a murine colon cancer model. Mice bearing subcutaneous tumors were administered adoptive T-cell transfer of CD62Lhigh or CD62Llow cells combined with an anti-CTLA-4 antibody (α-CTLA-4) or control immunoglobulin G. Subcutaneous tumors were harvested, and the antitumor effects and helper T-cell polarization were analyzed. CTLA-4 inhibition combined with CD62Lhigh cell administration showed the strongest antitumor effect. Combination therapy increased the number of CD3+ cells within the tumor. Moreover, CTLA-4 inhibition induced polarization of T cells infiltrating the tumor toward the T helper 1 lineage, and suppressed the frequency of regulatory T cells within the tumor, particularly in combination with CD62Lhigh T-cell transfer. This is the first report demonstrating that the efficacy of α-CTLA-4 and adoptive T-cell transfer combination therapy depends on the state of differentiation of the transferred T cells. Our data support the notion that a combination of α-CTLA-4 and adoptive T-cell transfer containing an abundance of naïve phenotype cells could potentially exert antitumor effects in a clinical setting.

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