In this study, we tested the effectiveness of the strategy of inhibiting the established immune checkpoints CTLA-4 (via CTLA-4 neutralization) or PD-1 (via neutralization of the PD-1 ligand PD-L1) in combination with targeting the intracellular checkpoint Cbl-b in order to enhance T cell anti-tumor activity in a B16ova melanoma mouse model (B16ova expresses PD-L1, not shown). The gene discussed is CBLB; the disease is melanoma.