Open AccessGlucocorticoid‐induced tumor necrosis factor receptor stimulation enhances the multifunctionality of adoptively transferred tumor antigen‐specific CD8 + T cells with tumor regression
Author(s) -
Imai Naoko,
Ikeda Hiroaki,
Tawara Isao,
Wang Linan,
Wang Lijie,
Nishikawa Hiroyoshi,
Kato Takuma,
Shiku Hiroshi
Publication year - 2009
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2009.01179.x
Subject(s) - cytotoxic t cell , tumor necrosis factor alpha , il 2 receptor , cancer research , immune system , immunotherapy , cd8 , immunology , biology , t cell , adoptive cell transfer , foxp3 , in vitro , biochemistry
We have reported for the first time the significance of effector T‐cell multifunctionality in antitumor immunity, suggesting that the appearance of multifunctional/polyfunctional tumor‐specific CD8 + T cells in vivo is a critical determinant of the success of antitumor immunotherapy, and a strategy to induce multifunctionality in effector cells is required for the successful immunotherapy of hosts with progressing tumor. Glucocorticoid‐induced tumor necrosis factor receptor (GITR) stimulation has been shown to enhance antitumor immune response. However, its functional impact on adoptively transferred T cells remains unclear. Here, we analyzed the impact of GITR stimulation in vivo on the functional profiles of adoptively transferred CD8 + T cells specific for murine fibrosarcoma CMS5. GITR stimulation was found to enhance multifunctionality (interferon (IFN)‐γ and tumor necrosis factor (TNF)‐α production and CD107a mobilization as a degranulation marker) in transferred cells at the single‐cell level. These cells exhibited upregulated expression of CD25 in draining lymph nodes and increased infiltration in tumor. Mice that received T‐cell therapy with GITR stimulation showed reduced Foxp3 + CD4 + T cells among tumor infiltrating lymphocytes and increased in vivo cytotoxic T lymphocytes (CTL) activity even with progressing tumor, resulting in enhanced tumor regression. These data strengthen the idea that effector T‐cell multifunctionality is a sensitive immune correlate for successful immunotherapy against malignancy and provide an immunological rationale for effective T‐cell therapy combined with GITR stimulation. ( Cancer Sci 2009; 100: 1317–1325)