Cancer Therapy: Preclinical Effective Anti-Neu–Initiated Antitumor Responses Require the Complex Role of CD4þ 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 CD8þ T cells in particular, has been established as a major factor for anti-HER2/neu–mediated tumor regression. However, the role of CD4þ T cells is still being defined. The purpose of this studywas to explorewhether and to what extent CD4þ T cells are involved in mediating the effects of anti-HER2/neu therapy. Experimental Design: The role of CD4þ T cells was examined using a transplant model of the rat HER2/ neu–overexpressing cell line TUBO. Tumor-bearingmice 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 CD8þ T cells, CD4þ T cells are also essential for anti-neu antibody-mediated tumor regression, but B cells are not required. The role for CD4þ cells is necessary throughout anti-neu therapy and not limited to helping CD8þ T cells. Expression of IFN-g is necessary for anti-neu therapy and IFN-g inducesMHC-II expression in TUBOcells promoting direct recognition byCD4þT cells. Furthermore, intratumoral depletion of CD4þ T cells or blockade of the activating cell-surface protein CD40L inhibits the