Abstract In the absence of a local inflammatory response, expression of MHC class II molecules is restricted mainly to hematopoietic cells and thymus epithelium. However, certain tumors, such as melanoma, may acquire aberrant constitutive expression of MHC class II. In a set of primary melanoma cell populations and correspondingly expanded autologous tumor-infiltrating lymphocytes (TIL), we show how MHC class II expression on melanoma cells associates with strong MHC class II–restricted CD4+ T-cell responses that are specific for tumors. Notably, we found that tumor-specific CD4+ T-cell responses were dominated by TNF production. TNF reduced CD8+ T-cell activation in IFNγ-rich environments resembling a tumor site. Conversely, direct CD4+ T-cell responses had no influence on either the proliferation or viability of melanoma cells. Taken together, our results illustrate a novel immune escape mechanism that can be activated by aberrant expression of MHC class II molecules, which by attracting tumor-specific CD4+ T cells elicit a local inflammatory response dominated by TNF that, in turn, inhibits cytotoxic CD8+ T-cell responses Cancer Res; 75(18); 3747–59. ©2015 AACR.