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    r> antibody elicits a significant increase in the M1 tumoricidal subset of macrophages in the TME (P < 0.05) while simultaneously trending toward a reduction in the M2 macrophage subset (P = 0.05) (Fig. 11B), thus contributing to overall antitumor actions of dual antiestrogen-ICI therapy.
    4. Discussion
    The role of estrogen signaling in the progression of BCs with ERα expression is well-established by the successful use of ER antagonists in the clinic [2,3,19]. In addition, the present findings indicate that anti-estrogens also have a significant effect on antitumor immunity in-dependent of their direct activity on BC cells. Although ICI have been shown to improve overall survival for subsets of patients with advanced melanoma, lung and TNBC [4,13], the bulk of patients with BC, parti-cularly ER-positive disease, do not have significant benefit from this promising therapeutic approach [4,14]. Despite known sex-related differences in immune responses [9,66,67], little is known about the 
    effect of sex hormones on immunotherapy in malignancy. An important question regarding the use of targeted therapies is whether these agents may positively or negatively affect immune cells. There is increasing awareness of the role of nonmalignant 958002-33-0 in the TME in regulating the tumor response to therapies. As indicated in the present report, the TME plays a critical role in modulating cancer progression and therapeutic responses. The presence of tumor-infiltrating lymphocytes in the TME is a prognostic indicator for benefit from ICI in TNBC, and T-cell in-hibitory pathways in the TME such as MDSC are identified [7,8,17]. Most immune cells including MDSC and CD8 + T-cells express estrogen receptors, ERα and ERβ, with ERα the predominant receptor type [7,8,10,11,17]. The accumulation of MDSC is a complex process in-volving expansion of immature myeloid cells and pathologic activation and conversion of immature cells to MDSC. Mechanistically, E2 sig-naling via JAK/STAT pathways may accelerate progression of E2-re-sponsive and -unresponsive tumors by driving the expansion of MDSC and enhancing their immunosuppressive activity in vivo as reported here and in previous work [7]. In contrast, blockade of E2 action
    Fig. 10. Tumor infiltrating lymphocytes (TILs) in 4T1 tumors from BALB/c mice, with CD8+ and CD4+ TILs shown. Single cell suspensions were purified, stained and analyzed by cyTOF. Groups include mice treated with control vehicle (CON), anti-PD-L1 antibody (Ab), fulvestrant (Fulv), JD128 or the combination of fulvestrant with anti-PD-L1 antibody (Fulv + Ab) or JD128 and anti-PD-L1 antibody (JD128 + Ab). A) Sequential gating strategy to analyze tumor CD3+ cell subsets. B) Z-scores of median intensity of distinct protein markers are show in heatmap for all clusters analyzed by Cytofkit. C) tSNE scatter plot visualization of CD3+ cells showing clusters of CD8+, CD4+ and Tregs (CD4+CD25+FoxP3+) cells are observed (upper left). Right: t-SNE plots with arcsinh transformed signal intensity of different activation markers. D) Percentage of different type of CD8+ and CD4+ T cells, naïve (nT) (CD44−CD62L+CD69−), effector (effT) (CD44+CD69+Tbethieomes−) and effector memory (TEM) (CD44+CD62L−). E) Increased expression of activation cytokines in CD8+ and CD4 + TILs population are shown. F) CD4+ CD25+FoxP3+ Tregs are significantly decreased by antiestrogen therapy. G) CD8 + TIL in the same tumor tissues used for cyTOF detected by IHC, with antiestrogens and combination treatment increasing CD8 infiltration in the tumor bed. *P < 0.05, **P < 0.01, *** P < 0.001, **** P < 0.0001. n=6-11.
    appears to delay tumor progression due to a decrease in MDSC numbers and immunosuppressive activity that promotes T-cell-dependent anti-tumor immunity. Our findings suggest that antiestrogens particularly when administered in combination with anti-PD-L1 antibodies act to inhibit BC progression in part by blocking the expansion and mobili-zation of MDSC that would otherwise promote tumor immune 
    tolerance. In addition, emerging findings show that serine/threonine protein kinase casein kinase 2 that is overexpressed in BC plays a cri-tical role in myeloid cell differentiation. Importantly, inhibition of casein kinase 2 disrupts the myeloid cell differentiation in BCs and enhances the efficacy of immunotherapy in mice [68]. This report is relevant to the present study because ERα signaling is known to
    Fig. 11. Combined therapy with JD128 and anti-PD-L1 antibody enhance tumor infiltrating dendritic cells and M1 macrophages. Single cell suspensions were purified, stained and ana-lyzed by cyTOF as described above. Groups include mice treated with control vehicle (CON), anti-PD-L1 antibody (Ab), fulvestrant (Fulv), JD128 or the combination of fulvestrant with anti-PD-L1 antibody (Fulv + Ab) or JD128 and anti-PD-L1 antibody (JD128 + Ab). A) Subset of dendritic cells present in the tumor bed show a significant increase in the total