Recently CD28 has been proven to be the main downstream target of PD-1- mediated signaling [1], and accordingly we have reported that a subset of Ag-specific CD8+ T-cell clones, characterized by PD-1 expression in the absence of CD28, show high proliferative capability and an AKT-dependent anti-tumor functionality sustained by ICOS [2-4]. This evidence concerns the gene CD28 and neoplasm.