br The current results also have implications
The current results also have implications for understanding po-tential gender-and/or age-dependent diﬀerences in tumor initiation and malignant progression. Humans show strong sex diﬀerences in im-munity to infection and autoimmunity, suggesting sex hormones play a role in regulating immune responses. Indeed, receptors for E2 regulate cells and pathways in the innate and adaptive immune system, as well as immune cell development  and T cell functions [11,79].
We note that ATP-competitive inhibitors of cyclin-dependent ki-nases 4/6 (CDK 4/6) such as abemaciclib were also reported to enhance the action of ICI. The mechanism for this eﬀect appears to involve modulation of T-cell activation and down-regulation of im-munosuppressive myeloid populations . This action may be de-pendent in part on the activity of E2, since E2 is well-known to sti-mulate expression/activity of cyclin D which is a requisite partner of CDK 4/6 to induce hyper-phosphorylation of Rb, thereby promoting cell proliferation and regulation of the Fluxametamide [84,85].
Results of this translational research indicate that SERDs with strong antiestrogen activity such as JD128 and fulvestrant and potentially other antiestrogens [86–89] can augment the action of immune checkpoint inhibitors to inhibit BC progression. This work provides a preclinical rationale for considering treatment combinations and sche-dules that include antiestrogens. Thus, use of antiestrogens together with ICI could lead to timely introduction of this dual treatment strategy in both ER-positive and potentially ER-negative or treatment-resistant breast cancers, thus significantly expanding the application and life-extending benefits of these drugs in the clinic to promote pa-tient survival.
This work was funded by the Tower Cancer Research Foundation-
Jessica M. Berman Breast Cancer Fund, NIH/NCI U54 CA143930Charles Drew University School of Medicine-UCLA Jonsson Cancer Center Partnership, California Breast Cancer Research Program, Hickey Foundation and in part by the CDMRP DOD BCRP BC181420 a C. We thank Dr. Hermes J. Garbán for thoughtful discussions, Dr. Antoni Ribas for use of research resources for this project, Mr. Colin Sterling, Jr. for laboratory contributions and Dr. Dinesh Rao for gui-dance in hematopathology issues.
Appendix A. Supplementary data
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Fig. 12. Estrogen (E2) (left panel) orchestrates a number of eﬀects on immune cells in the TME. Evidence suggests that E2 promotes tumor immune tolerance through inhibition of CD8+ and CD4 + T cell eﬀector responses, as well as antigen-presenting cells such as M1 macrophages and dendritic cells (DC). In addition, E2 signaling also stimulates suppressive actions of MDSC that can increase Tregs and M2 macrophages for tumor-promotion. In contrast, antiestrogen therapy with SERDs (right panel), particu-larly when used in combination with immune checkpoint in-hibitors, helps to reverse the several actions of E2 and may re-present a novel option in combination with immune checkpoint inhibitors to overcome an immunosuppressive BC microenviron-ment and stimulate more eﬀective anti-tumor responses.
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