In the present study, we investigate anti-tumor functions of TR-CD4 and demonstrate that direct cognate interaction between this subset of human CD4+ T helper cells (TR-CD4) and cancer cells efficiently induce growth arrest in cancer cells and potently provide help to cognate tumor antigen-specific CD8+ T cells in an APC-independent fashion, resulting in significant anti-tumor activity both in vitro and in vivo. Here, CD8A is linked to cancer.