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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

TAKESHI ISHIKAWA, SATOKO ADACHI, TETSUYA OKAYAMA, SATOSHI KOKURA, KATSURA MIZUSHIMA, TOSHIFUMI DOI, TATSUZO MATSUYAMA, NAOYUKI SAKAMOTO, KAZUHIRO KATADA, KAZUHIRO KAMADA, KAZUHIKO UCHIYAMA, OSAMU HANDA (+4 others)
2015 Oncology Reports  

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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
more » ... l. Mice bearing subcutaneous tumors were administered adoptive T-cell transfer of CD62L high or CD62L low 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 CD62L high 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 CD62L high 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.
doi:10.3892/or.2015.3815 pmid:25738564 fatcat:xmjykksntnfdbnfyngrvqc57ey
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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. "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." Oncology Reports 33.5 (2015) 2545-2552