Methods and compositions comprising fragments of the programmed death-1 protein (PD-1) ectodomain for inhibiting and/or interfering with interactions between PD-1 (also known as CD279) and programmed death-ligand 1 (PD-L1) and/or programmed death-ligand 2 (PD-L2) are disclosed. In addition, methods and compositions for increasing IL-2 levels in a cell, and methods and compositions for preventing, treating, or ameliorating the effects of cancer in a subject, are disclosed.