As in all treatments that involve checkpoint inhibition in human cancer therapy, the use of T cells in which Cbl-b is inactivated will require a close watch for the development of autoimmune diseases Nevertheless, our results suggest that targeting Cbl-b in cancer immunotherapy offers the opportunity to simultaneously override numerous relevant “checkpoints” including sensitivity to regulatory T cells, suppression by TGF-β, and immune regulation not only by CTLA-4 (because of the CD28-independence of Cbl-b−/− T cells) but also, as we now report, immune regulation by the PD-L1/PD-1 pathway. This evidence concerns the gene CD28 and cancer.