The Selective Estrogen Receptor Modulators, Tamoxifen and Raloxifene, Impair Dendritic Cell Differentiation and Activation

Abstract

Most immune cells, including myeloid progenitors and terminally differentiated dendritic cells (DC), express estrogen receptors (ER) making these cells sensitive to estrogens. Our laboratory recently demonstrated that 17-β-estradiol (E2) promotes the GM-CSF-mediated development of CD11c+CD11bint DC from murine bone marrow precursors. We tested whether the therapeutic selective estrogen receptor modulators (SERM), raloxifene and tamoxifen, can perturb DC development and activation. SERM, used in treatment of breast cancer and osteoporosis, bind to ER and mediate tissue-specific agonistic or antagonistic effects. Raloxifene and tamoxifen inhibited the differentiation of estrogen-dependent DC from bone marrow precursors ex vivo in competition experiments with physiological levels of E2. DC differentiated in the presence of SERM were assessed for their capacity to internalize fluoresceinated Ags as well as respond to inflammatory stimuli by increasing surface expression of molecules important for APC function. Although SERM-exposed DC exhibited increased ability to internalize Ags, they were hyporesponsive to bacterial LPS: relative to control DC, they less efficiently up-regulated the expression of MHC class II, CD86, and to a lesser extent, CD80 and CD40. This phenotype indicates that these SERM act to maintain DC in an immature state by inhibiting DC responsiveness to inflammatory stimuli. Thus, raloxifene and tamoxifen impair E2-promoted DC differentiation and reduce the immunostimulatory capacity of DC. These observations suggest that SERM may depress immunity when given to healthy individuals for the prevention of osteoporosis and breast cancer and may interfere with immunotherapeutic strategies to improve antitumor immunity in breast cancer patients.

Numerical and functional defects of blood dendritic cells in early- and late-stage breast cancer

“…It is plausible, however, that ongoing adjuvant anti-oestrogen therapy may have had an effect on the prolonged decrease in peripheral DC in these patients. In fact, it has been shown that anti-estrogens (such as Tamoxifen) inhibit the in vitro functional differentiation of human monocytes (Komi and Lassila, 2000), synovial macrophages (Komi et al, 2001) and murine splenic monocytes (Nalbandian et al, 2005) into DC, and affect basic immunological functions such as cytokine and chemokine expression (Bengtsson et al, 2004). However, there is no evidence as yet to suggest blood DC levels are affected by oestrogen inhibitors in vivo.…”

Estrogen Selectively Promotes the Differentiation of Dendritic Cells with Characteristics of Langerhans Cells

“…TLR4 is the TLR responsive to LPS. Interestingly, the level of surface TLR4 expression was lower on the CD11b int Ly6C Ϫ DC, indicating that the level of TLR4 expression does not correlate with the extent of LPS-responsiveness (30).…”

“…Our experiments with the ER antagonist ICI 182,780, selective ER modulators, and ER␣ Ϫ/Ϫ BM cells indicated that estrogen acts via the ER to promote DC differentiation (29,30 …”

Microtubule-Depolymerizing Agents Used in Antibody–Drug Conjugates Induce Antitumor Immunity by Stimulation of Dendritic Cells

“…Similarly, vinblastine was found to promote DCmediated antigen presentation and tumor antigen-specific Tcell responses in vitro and in tumor-bearing hosts (15,16). In contrast, other cytotoxic drugs may block DC maturation, thereby antagonizing antitumor immunity (34,35). Yet, the mechanism proposed here seems to be distinct from direct effects on DCs that have been described using low noncytotoxic concentrations of other classes of cytotoxic drugs (36).…”