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

• Published in: Oncology reports Vol. 33; no. 5; pp. 2545 - 2552
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.05.2015; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: adoptive T-cell therapy; Adoptive Transfer - methods; Animals; Antigens; Antigens, CD - immunology; Antineoplastic Agents - immunology; Cancer therapies; Cell cycle; Cell Differentiation - immunology; Cell Line, Tumor; Cell- and Tissue-Based Therapy - methods; Cellular proteins; Cellular therapy; Chemotherapy; Clinical trials; Colorectal cancer; CTLA-4 antibody; CTLA-4 Antigen - immunology; Cytotoxicity; Flow cytometry; Gene expression; Genotype & phenotype; Health aspects; Immune system; Immunoglobulins; Laboratories; Ligands; Lymphocyte Activation - immunology; Lymphocytes; Male; Melanoma; Methods; Mice; Mice, Inbred BALB C; naïve T-cell; Patient outcomes; Penicillin; Properties; Rodents; Studies; T cell receptors; T helper 1; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Regulatory - immunology; Tumors; United States > US
• ISSN: 1021-335X; 1791-2431
• DOI: 10.3892/or.2015.3815

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.