In tumor cells, thyroid hormone analogues non-immunologically regulate PD-L1 and PD-1 accumulation that is anti-apoptotic

Abstract

The PD-1/PD-L1 immune checkpoint involving tumor cells and host immune defense lymphocytes is a well-studied therapeutic target in oncology. That PD-1 and PD-L1 may have additional functions within tumor cells that are independent of the checkpoint is indicated by actions of a thyroid hormone analogue, L-thyroxine (T4), on these checkpoint components. Acting at a cell surface receptor on plasma membrane integrin αvβ3, T4 stimulates intracellular accumulation of PD-L1 in cancer cells. In these thyroid hormone-treated cells, T4-induced PD-L1 is non-immunologically anti-apoptotic, blocking activation of p53. Several laboratories have also described accumulation of PD-1 in a variety of cancer cells, not just immune defense lymphocytes and macrophages. Preliminary observations indicate that T4 stimulates intracellular accumulation of PD-1 in tumor cells, suggesting that, like PD-L1, PD-1 has non-immunologic roles in the setting of cancer. Where such roles are anti-apoptotic, thyroid hormone-directed cancer cell accumulation of PD-1 and PD-L1 may limit effectiveness of immunologic therapy directed at the immune checkpoint.

Development of a prognostic index based on an immunogenomic landscape analysis of papillary thyroid cancer

“…At present, cutting-edge immunotherapies promise PTC patients another alternative treatment method. In vitro and/or in vivo experiments proposed that immune checkpoint inhibitors could boost the effective elimination of thyroid tumor cells [22,23]. Besides, Bai Y et al found that the expression of BRAF V600E is positively correlated with PD-L1/PD-1 in PTC samples, which indicated that immune checkpoint therapy might be effective for PTC patients with the BRAF V600E mutation [24].…”

Development of a Prognostic Index Based on an Immunogenomic Landscape Analysis of Papillary Thyroid Cancer

“…At present, cutting-edge immunotherapies promise PTC patients another alternative treatment method. In vitro and/or in vivo experiments proposed that immune checkpoint inhibitors could boost the effective elimination of thyroid tumor cells [22,23]. Besides, Bai Y et al found that the expression of BRAF V600E is positively correlated with PD-L1/PD-1 in PTC samples, which indicated that immune checkpoint therapy might be effective for PTC patients with the BRAF V600E mutation [24].…”

Association between programmed cell death ligand 1 expression and thyroid cancer

“…In other words, the positive expression of PD-L1 seems to indicate that the type of thyroid cancer originates from thyroid follicular epithelial cells. Lin et al [ 30 ] reported that acting at a cell surface receptor on plasma membrane integrin αvβ3, thyroxine produced by thyroid follicular epithelial cells stimulates intracellular accumulation of PD-L1 in cancer cells and induces downstream signaling pathways that promote tumor cell proliferation, such as mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase and phosphatidylinositol-3-kinase/protein kinase B pathways, which can promote PD-L1 overexpression. Our results on OS differ from those of Girolami study [ 16 ] ; unfortunately, our study on OS only included 3 articles, which may have affected the final result.…”