Thus, PD-1 engagement with PD-L1 interferes with TCR signal transduction and co-stimulation by recruiting the SHP-1 and SHP-2 phosphatases to the intracellular domain of PD-183,84 and up-regulating the expression of CBL E3 ubiquitin ligases to induce TCR down-modulation.5,85,86 However, the direct protective role of PD-L1 expression in cancer cells has thus far been neglected, thereby missing an opportunity for targeted therapies that directly interfere with PD-L1 signal transduction pathways in cancer cells. Here, CBL is linked to cancer.