The Effects of Tamoxifen on Tolerogenic Cells in Cancer

SIMPLE SUMMARY: Tamoxifen is a very well-known hormonal therapy used to treat breast cancer patients. It works by blocking the effects of estrogen in breast tissue by competing with estradiol (E(2)) in the receptor site and binding to DNA to inhibit carcinogenesis. Moreover, it is less clarified that TAM is also involved indirectly via a Foxp3 knockout model through the CreER system to target specific immune checkpoints, especially checkpoints arising in cancer therapy. The suppressive function of tolerogenic cells is very important in the TME. Hence, in our study, we observed the effects of TAM on Tregs, in which it is involved indirectly via the CreER system. In addition, we also review the effects of TAM on other cells, which are MDSCs and DCs, that act by bridging the innate and adaptive immune systems. ABSTRACT: Tamoxifen (TAM) is the most prescribed selective estrogen receptor modulator (SERM) to treat hormone-receptor-positive breast cancer patients and has been used for more than 20 years. Its role as a hormone therapy is well established; however, the potential role in modulating tolerogenic cells needs to be better clarified. Infiltrating tumor-microenvironment-regulatory T cells (TME-Tregs) are important as they serve a suppressive function through the transcription factor Forkhead box P3 (Foxp3). Abundant studies have suggested that Foxp3 regulates the expression of several genes (CTLA-4, PD-1, LAG-3, TIM-3, TIGIT, TNFR2) involved in carcinogenesis to utilize its tumor suppressor function through knockout models. TAM is indirectly concomitant via the Cre/loxP system by allowing nuclear translocation of the fusion protein, excision of the floxed STOP cassette and heritable expression of encoding fluorescent protein in a cohort of cells that express Foxp3. Moreover, TAM administration in breast cancer treatment has shown its effects directly through MDSCs by the enrichment of its leukocyte populations, such as NK and NKT cells, while it impairs the differentiation and activation of DCs. However, the fundamental mechanisms of the reduction of this pool by TAM are unknown. Here, we review the vital effects of TAM on Tregs for a precise mechanistic understanding of cancer immunotherapies.