To investigate the mechanism of action of PDI-1, we analyzed its binding to PD-1 and PD-L1 proteins in vitro and its ability to rescue TCR/CD28-dependent activation of T cells ex vivo and in vivo using melanoma and non-small-cell lung cancer (NSCLC) cell lines and mouse tumor models. The gene discussed is PDCD1; the disease is non-small cell lung carcinoma.