Abstract B37: Anti-PD-L1 activity of Nano-diamino-tetrac (Nanotetrac) on cancer cells
Authors: Yu-Tang Chin, Hsuan-Yu Lai, Heng-Yuan Tang, Hung-Yun Lin, Shaker A. Mousa, Paul J. Davis
Journal: Cancer Research (2016)

Abstract The PD-1 (programmed death-1)/PD-L1 (PD-ligand 1) checkpoint is a critical regulator of activated T cell-cancer cell interactions, serving to defend tumor cells against immune destruction. PD-L1 (or B7-H1) produced by tumor cells engages PD-1 to suppress activated T cell engagement with tumor cells, but also to induce apoptosis of T cells. Overexpression of PD-L1 is observed in melanoma, pancreatic and lung cancers, among others, and may correlate with decreased survival (P. Wu et al., PLoS One 2015; 10(6):e0131403). Antibodies directed to PD-L1 have shown promise as immunotherapy for melanoma, lung and kidney cancers and hematological malignancies (D.B. Page et al., Ann Rev Med 2014; 65:185-202). Activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K) signal transducing pathways is critical to expression of the PD-L1 gene in cancer cells and interferon-γ (IFN-γ) is a potent endogenous inducer of expression of PD-L1. 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. The integrin is generously expressed by cancer cells and dividing endothelial cells, but not by nondividing, nonmalignant cells. NDAT is made by covalently bonding via a linker of tetrac (tetraiodothyroacetic acid), a derivative of L-thyroxine (T4), to poly(lactic-co-glycolic acid)(PLGA) to limit its action to the receptor on integrin αvβ3. NDAT inhibits the PI3-K and MAPK pathways in cancer cells and blocks expression of a panel of genes critical to cancer cell survival pathways. Tetrac is also known to block enhancement by thyroid hormone of actions of IFN-γ. We therefore examined the actions in vitro of T4 and NDAT on PD-L1 mRNA (qPCR) on human colon carcinoma (HCT116) cells and breast cancer (MDA-MB-231) cells. In HCT116 cells, T4 (10-7 M total; 10-10 M free hormone) increased PD-L1 gene expression by 100% (P &amp;lt;0.01). NDAT (10-7 M tetrac-equivalent) reduced basal level PD-L1 expression by 45% and T4-stimulated PD-L1 by 75% (each reduction, P &amp;lt;0.01). In MDA-MB-231 cells, T4-stimulated PD-L1 expression by 40% and NDAT reduced this enhancement by 50% (P &amp;lt;0.01). NDAT did not affect basal level PD-L1 gene expression in these cells. The absence of this effect is under investigation, particularly, the state of activation of αvβ3 in MDA-MB-231 cells. Thus, NDAT significantly and non-immunologically suppresses T4-induced PD-L1 gene expression in human colon and breast cancer cells. Nonmalignant cells and normal immune system surveillance will escape this novel effect of NDAT because normal cells, except for rapidly dividing endothelial cells, express little αvβ3. In the clinical setting, the gene is invariably exposed to host thyroid hormone and we speculate that T4 supports defensive PD-1/PDL1 checkpoint activity in tumor cells. Citation Format: Yu-Tang Chin, Hsuan-Yu Lai, Heng-Yuan Tang, Hung-Yun Lin, Shaker A. Mousa, Paul J. Davis. Anti-PD-L1 activity of Nano-diamino-tetrac (Nanotetrac) on cancer cells. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B37.