Effective anti-neu-initiated antitumor responses require the complex role of CD4+ T cells.

PURPOSE Targeting oncogenic receptors with antibodies has been thought to suppress tumor growth mainly by interrupting oncogenic signals. Recently, the essential role for adaptive immunity, and CD8(+) T cells in particular, has been established as a major factor for anti-HER2/neu-mediated tumor regression. However, the role of CD4(+) T cells is still being defined. The purpose of this study was to explore whether and to what extent CD4(+) T cells are involved in mediating the effects of anti-HER2/neu therapy. EXPERIMENTAL DESIGN The role of CD4(+) T cells was examined using a transplant model of the rat HER2/neu-overexpressing cell line TUBO. Tumor-bearing mice were treated with anti-neu therapy in conjunction with CD4 depletion or CD40L blockade. The effects of CD4 depletion on the antitumor response were examined by tumor growth analysis and enzyme-linked immunospot (ELISPOT). RESULTS In addition to CD8(+) T cells, CD4(+) T cells are also essential for anti-neu antibody-mediated tumor regression, but B cells are not required. The role for CD4(+) cells is necessary throughout anti-neu therapy and not limited to helping CD8(+) T cells. Expression of IFN-γ is necessary for anti-neu therapy and IFN-γ induces MHC-II expression in TUBO cells promoting direct recognition by CD4(+) T cells. Furthermore, intratumoral depletion of CD4(+) T cells or blockade of the activating cell-surface protein CD40L inhibits the antitumor response. CONCLUSIONS This study reveals the essential role of CD4(+) T cell for anti-neu-mediated tumor regression.