br activate transcription of casein kinase and ER antagonist
activate transcription of casein kinase 2 , and ER antagonists block this action.
In general, MDSC are not present in healthy individuals but occur in pathologic states associated with chronic inflammation and cancer . For example, BC biopsies from patients with residual disease after chemotherapy contain relatively high levels of infiltrating myeloid-derived HBX 41108 . Of note, these mechanisms may also be important during pregnancy, where E2 may drive the expansion/activation of MDSC to promote maternal-fetal immune tolerance [70,71]. Im-portantly, the current findings provide evidence in preclinical human and murine models that blockade of E2 signaling acts to inhibit the expansion of MDSCs that are major contributors to pathologic myelo-poiesis and immune tolerance in BC [7,17]. In addition, ovariectomized mice with E2 depletion have significantly reduced progression of murine E2-insensitive TNBCs when grown as implants in syngeneic immune-intact mice. These results are consistent with earlier reports on the crucial role of MDSC and TILs on modulating antitumor immunity . Antitumor immunity includes several functional steps required for an immune response to eliminate tumors, such as blockade of im-munosuppression, promotion of immune infiltration, activation of an-tigen-presenting cells and enhancement of eﬀector cell activity . The presence of TILs in the TME is predictive of patient survival. Sev-eral types of CD45+ leukocytes infiltrate the TME including CD4+ and CD8 + T-cells identified by specific phenotypic markers. It is re-cognized that eﬀective antitumor immune responses require the in-volvement of both CD4+ and CD8 + T cells, with CD4 + T cells critical for priming of tumor-specific CD8 + T cells and for the secondary ex-pansion and memory of CD8 + T cells . However, CD4+FoxP3+ Treg cell-induced immune suppression represents a major obstacle for successful antitumor immunity. Accordingly, our data show that anti-estrogens stimulate increments in the levels of eﬀector and eﬀector memory CD8+ and CD4 + T cells, while simultaneously suppressing the levels of immunosuppressive CD4+FoxP3+Treg cells. Further-more, MDSC are reported in turn to suppress antitumor activities of eﬀector and memory eﬀector CD8 + T-cells in vivo  and other natural immune cells such as macrophages and dendritic cells [70,74], actions that appear to be reversed on treatment with antiestrogens combined with ICI in murine models in vivo. As suggested from our findings, cytokine secretion modulated by antiestrogen therapy may also play a role as functional chemo-attractants for selected immune cells. Hence, the current data provide evidence that beneficial anti-tumor eﬀects occur on treatment of murine TNBCs with antiestrogens combined with ICI in syngeneic, immune-intact mice, including pro-motion of eﬀector and memory eﬀector T-cells in the TME and mod-ulation of macrophage and dendritic cell subsets. Thus, SERDs that enhance and/or maintain the activation status of eﬀector T-cells may be used in dual therapies to enhance the eﬀects of ICI. A schematic re-presentation of postulated eﬀects of E2 and antiestrogen signaling on immune cells in the TME is shown in Fig. 12. r> Tumor mutational burden (TMB) and the expression of immune checkpoints such as PD-L1 also play an important role in determining
tumor sensitivity to ICI [4,13,75]. Reduced TMB and low expression of PD-L1 may be important factors that explain the relative resistance of most BCs to ICI therapies [4,14]. In this regard, recent reports indicate that immunotherapeutic target expression on BCs such as α-lactal-bumin, a lactation protein negatively regulated by E2, can be amplified several-fold by antiestrogen therapy and thereby potentially enhance the eﬃcacy of ICI if combined with antiestrogens . In addition, estrogens are also found to modulate the expression of PD-L1 in en-dometrial tissues [77,78], in immune cells from reproductive tract and in ER-positive BC cells in vitro [79,80]. The latter indicates that E2 may upregulate PD-L1 expression in ERα-positive BC cells to potentially suppress immune functions of T-cells in the TME and drive cancer progression. Of note, only 19.4% of patients with ER-positive/HER2-negative BCs were found to be PD-L1 positive in recent clinical trials, while 58.6% of TNBC patients screened in trials were PD-L1 positive [14,81]. This diﬀerence in PD-L1 expression may account in part for a corresponding diﬀerence in clinical responses to ICI treatment. These reports raise the possibility of using antiestrogens as a priming ap-proach to reverse immune-resistant ‘cold’ BCs to immune-sensitive ‘hot’ tumors more likely to respond to ICI.