Cancer immunotherapy, particularly PD-1/PD-L1 blockade, has seen remarkable success. However, patients can develop adaptive resistance to this treatment. To improve efficacy, combination strategies like pairing PD-1/PD-L1 blockade with radiotherapy or chemotherapy were explored. Additionally, new immune checkpoints such as TIGIT, LAG-3, TIM-3, and CD47 have been discovered. Of these, TIGIT shows potential as a target due to its presence on both immune and tumor cells. Noticeably, Liothyronine, an active form of thyroid hormone, can bind PVR and blocks the interaction of TIGIT/PVRn. Besides, Liothyronine enhances CD4+ and CD8+ T cell function in PBMCs. The anti-tumor effects of Liothyronine rely on CD4+ T cells, CD8+ T cells, and NK cells.

Liothyronine is a TIGIT/PVR blocker for cancer and immunity research.

In vitro, Liothyronine inhibits PVR and TIGIT binding in a dose-dependent manner (IC50 of 6.1 μM). It also interacts with thyroid hormone receptors TRα and TRβ (Kis: 2.33 nM for hTRα and 2.29 nM for hTRβ). While not affecting tumor cell growth, Liothyronine notably boosts T cell activity. When added to stimulated PBMCs at 100 μM, Liothyronine significantly enhances IFN-γ secretion by CD4+ and CD8+ T cells. Moreover, in hepatocarcinoma cells with TRβ1 overexpression, Liothyronine at 100 nM promotes cell proliferation.

In MC38 tumor model mice, Liothyronine (1.5 and 5 mg/kg, i.p., every other day) inhibits tumor growth and boosts immune response. Different doses of Liothyronine (0.5, 1.5, 5, 15 mg/kg) were tested, with 0.5 mg/kg showing minimal anti-tumor effects, while 5 and 15 mg/kg were equally effective. Moreover, Liothyronine significantly increases CD8+ T cell presence within tumors and enhances IFN-γ secretion by these cells when treated with high-dose Liothyronine. Overall, Liothyronine suppresses tumor growth and promotes CD8+ T cell responses in tumor-bearing mice. In summary, Liothyronine blocks both human and mouse TIGIT/PVR interaction, and exerts anti-tumor effects by TIGIT/PVR blockade.

References:

[1] Zhou X, et al. Repositioning liothyronine for cancer immunotherapy by blocking the interaction of immune checkpoint TIGIT/PVR. Cell Commun Signal. 2020 Sep 7;18(1):142.

[2] Lin KH, et al. Stimulation of proliferation by 3,3′,5-triiodo-L-thyronine in poorly differentiated human hepatocarcinoma cells overexpressing beta 1 thyroid hormone receptor. Cancer Lett. 1994 Oct 14;85(2):189-94.