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

Hung Yun Lin, Yu-Tang Chin, André Wendindondé Nana, Ya-Jung Shih, Hsuan-Yu Lai, Heng-Yuan Tang, Matthew Leinung, Shaker A. Mousa, Paul J. Davis

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

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 (10-7 M total; 10-10 M free hormone) stimulated PD-L1 gene expression by 38% and increased PD-L1 protein by 2.7-fold (p -7 M) reduced PD-L1 in T4-exposed cells by 21% (mRNA) and 39% (protein) (p 4 enhanced PD-L1 gene expression by 17% and protein content by 24% (p 4-treated cells lowered mRNA by 33% and protein by 66%. In HT-29 cells, T4 increased 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 4-induced PD-L1 accumulation. We propose that, by a nongenomic mechanism, endogenous T4 may 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.

Original languageEnglish
JournalSteroids
DOIs
Publication statusAccepted/In press - Jan 28 2016

Keywords

  • Breast carcinoma
  • Cancer immunotherapy
  • Colon carcinoma
  • l-Thyroxine (T)
  • Programmed death ligand 1

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Molecular Biology
  • Organic Chemistry
  • Pharmacology

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