title: Actions of l-thyroxine and Nano-diamino-tetrac (Nanotetrac) on PD-L1 in cancer cells.
abstract: 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<0.05, all changes). NDAT (10-7M) reduced PD-L1 in T4-exposed cells by 21% (mRNA) and 39% (protein) (p<0.05, all changes). In HCT116 cells, T4enhanced PD-L1 gene expression by 17% and protein content by 24% (p<0.05). NDAT reduced basal PD-L1 mRNA by 35% and protein by 31% and in T4-treated cells lowered mRNA by 33% and protein by 66%. In HT-29 cells, T4increased PD-L1 mRNA by 62% and protein by 27%. NDAT lowered basal and T4-stimulated responses in PD-L1 mRNA and protein by 35-40% (p<0.05). Activation of ERK1/2 was involved in T4-induced PD-L1 accumulation. We propose that, by a nongenomic mechanism, endogenous T4may clinically support activity of the defensive PD-1/PD-L1 checkpoint in tumor cells. NDAT non-immunologically suppresses basal and T4-induced PD-L1 gene expression and protein accumulation in cancer cells.
authors.affiliation: PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hung-Yun
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan; Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Tang
authors.initials: YT
authors.lastname: Chin
authors.affiliation: PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: André Wendindondé
authors.initials: AW
authors.lastname: Nana
authors.affiliation: Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ya-Jung
authors.initials: YJ
authors.lastname: Shih
authors.affiliation: Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Lai
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA; NanoPharmaceuticals LLC, Rensselaer, NY, USA.
authors.forename: Heng-Yuan
authors.initials: HY
authors.lastname: Tang
authors.affiliation: Department of Medicine, Albany Medical College, Albany, NY, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Leinung
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA; NanoPharmaceuticals LLC, Rensselaer, NY, USA.
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA; NanoPharmaceuticals LLC, Rensselaer, NY, USA; Department of Medicine, Albany Medical College, Albany, NY, USA. Electronic address: pdavis.ordwayst@gmail.com.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Davis
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013974:Thyroxine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D012333:RNA, Messenger; C011126:tetraiodothyroacetic acid; D013974:Thyroxine
keywords: Breast carcinoma; Cancer immunotherapy; Colon carcinoma; Programmed death ligand 1; l-Thyroxine (T(4))