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 inTUBOcells promoting direct recognition byCD4 ⁺ 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.