In this context, it has previously been shown that PD-1 signaling causes dephosphorylation of TCR proximal molecules and subsequent transcriptional inhibition.13,41,59 Targeting of components involved in these regulatory mechanisms, such as SHP2, MARCH5 and USP5, may increase the efficacy of cancer immunotherapy by PD-1 blockade and the γc family cytokines (Fig. 8). The gene discussed is USP5; the disease is cancer.