Actions of l-thyroxine and Nano-diamino-tetrac (Nanotetrac) on PD-L1 in cancer cells

•Clinical disruption of the PD-1/PD-L1 checkpoint in tumor cells has relied upon antibody to PD-L1 protein.•Thyroid hormone (l-thyroxine, T4) stimulates PD-L1 gene expression in tumor cells.•This T4 action is initiated at the T4-tetrac receptor on the extracellular domain of integrin αvβ3.•Tetrac as a nanoparticle formation (NDAT) acts at the integrin to downregulate PD-L1 gene expression. The PD-1 (programmed death-1)/PD-L1 (PD-ligand 1) checkpoint is a critical regulator of activated T cell-cancer cell interactions, defending tumor cells against immune destruction. Nano-diamino-tetrac (NDAT; Nanotetrac) is an anticancer/anti-angiogenic agent targeted to the thyroid hormone-tetrac receptor on the extracellular domain of integrin αvβ3. NDAT inhibits the cancer cell PI3-K and MAPK signal transduction pathways that are critical to PD-L1 gene expression. We examined actions in vitro of thyroid hormone (l-thyroxine, T4) and NDAT on PD-L1 mRNA abundance (qPCR) and PD-L1 protein content in human breast cancer (MDA-MB-231) cells and colon carcinoma (HCT116 and HT-29) cells. In MDA-MB-231 cells, a physiological concentration of T4 (10−7M total; 10−10M free hormone) stimulated PD-L1 gene expression by 38% and increased PD-L1 protein by 2.7-fold (p