Editors' ChoiceCancer

Tamoxifen as an immunotherapy

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Sci. Signal.  14 Feb 2017:
Vol. 10, Issue 466, eaam9611
DOI: 10.1126/scisignal.aam9611

Antiestrogen drugs may treat some estrogen receptor–negative tumors by limiting the proliferation and activity of suppressive immune cells.

Estrogen signaling accelerates the progression of some breast cancers, thus patients with estrogen receptor (ER)–positive tumors are treated with tamoxifen, an ER partial agonist that inhibits estrogen-mediated ER activation. However, it is less effective in patients with ER-positive ovarian cancer, and it is not given to patients with ER-negative breast cancer. Consequently, tamoxifen has not been studied in ovarian cancer patients with ER-negative tumors. Svoronos et al. found that antiestrogen compounds may be effective in some patients with ER-negative tumors. Ovarian tumors often have substantial infiltration of myeloid-derived immune suppressor cells (MDSCs) and inflammatory dendritic cells with immunosuppressive activity. In cultured bone marrow–derived myeloid precursor cells from mice and cancer patients, ERα-dependent estrogen signaling promoted the JAK2-STAT3 pathway, which stimulated the differentiation and immunosuppressive activity of MDSCs. Bioinformatics analysis of ovarian cancer tumor samples revealed that expression of the gene encoding an estrogen biosynthesis enzyme correlated with decreased markers of cytotoxic T cell activity and infiltration. In a mouse model of ERα-negative ovarian cancer, removal of the ovaries or treatment with tamoxifen decreased the number of MDSCs and increased the number of effector and cytotoxic T cells that infiltrated the tumor and prolonged animal survival, whereas the opposite effects were seen in response to estradiol. However, these effects were not observed in Esr1 (ERα) knockout, Rag1 knockout, or MDSC-depleted mice, indicating that ERα signaling in the adaptive immune system mediated the tumor-suppressive effects of tamoxifen and the tumor-promoting effects of estrogen. These phenomena were also seen in syngeneic mice injected with tamoxifen-insensitive melanoma, lung, and mammary cancer cells. As a partial ER agonist, tamoxifen causes side effects in patients; thus, knowing which patients are most likely to benefit from tamoxifen and how to maximize its efficacy is critical. In addition to indicating that tamoxifen may be used as an immunotherapy in patients with ER-negative tumors, the findings highlight that patient stratification should consider drug responsiveness in cells of the tumor microenvironment as well as drug sensitivity of the tumor cells.

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