Abstract 5953: Reshaping the tumor microenvironment: new application of tamoxifen in triple negative breast cancer immunomodulation
Authors: Lee Pony Yu-Ling , Aberin Marvin A. , Shen Chien-Chang , Lin Kun-Yuan , Chang Chao Di , Yang Chih-Chieh , Cheng Shan-Yun , Hung Ya Wen , Hsu Xin-Guo , Wang Shu-Ping 
Published: April 2023

Abstract
Tamoxifen is a widely known estrogen receptor (ER) modulator which has been employed in adjuvant treatment of ER+ breast cancer for over 30 years. Interestingly, clinical observations reveal that tamoxifen is capable of inducing regression of some tumors lacking ER expression whereas tamoxifen is also capable of increasing host resistance against cancer in an ER-independent mechanism. These findings suggest the immunomodulatory effects of tamoxifen may be ER-independent, but little is known about the underlying mechanism and the potential clinical implication. Recently, we identified a novel mechanism by which tamoxifen exerts its DNA-damaging potential by re-shaping the unfavorable tumor microenvironment in breast cancer. A long-term tamoxifen administration induces downregulation of the chromatin ‘‘reader’’ RACK7/ZMYND8, which acts as a suppressor of interferon-stimulated genes (ISGs, including cytokines and chemokines) and CEACAM1 in both ER+ and triple negative breast cancer (TNBC) cells. To investigate the immunomodulatory effects of tamoxifen in conjunction with RACK7-knockdown, the orthotopic murine TNBC 4T1 model was employed to investigate tamoxifen-mediated cellular modulation in TNBC. The control and RACK7-knockdown 4T1 cells are orthotopically implanted into the mammary fat pad of female BALB/c mice. Peripheral cytokines/chemokines and high-content biomarker studies (multiplex immunoassays, flow cytometry, and single-cell RNA sequencing) are deployed to obtain insights into the mechanistic rationale behind the immunomodulatory effects of tamoxifen and/or RACK7-knockdown. The tamoxifen-mediated cellular modulation evokes cytokine/chemokine secretion and further induces T-cell infiltration into tumor area. However, tumor reduction was limited due to extensive T-cell exhaustion from interaction of CEACAM1 and TIM-3, a “checkpoint” receptor expressed in CD4+ and CD8+ T cells. The expression patterns of CEACAM1 and PD-L1 in 4T1 tumor cells and that of TIM-3 and PD-1 in CD4+ and CD8+ T-cells correlate with intra-tumor infiltration of T-cells and tumor cell growth. Therefore, targeting the interaction between CEACAM1 and TIM-3 to overcome T-cell exhaustion is crucial for the new therapeutic role of tamoxifen treatment in TNBC breast cancer in conjugation with RACK7-knockdown. Altogether, our findings provide direct evidence to support a new therapeutic opportunity by targeting CEACAM1-TIM-3 interaction in the tamoxifen-mediated tumor immune microenvironment for improving immune checkpoint blockade therapy in breast cancer.
Citation Format: Pony Yu-Ling Lee, Marvin A. Aberin, Chien-Chang Shen, Kun-Yuan Lin, Chao Di Chang, Chih-Chieh Yang, Shan-Yun Cheng, Ya Wen Hung, Xin-Guo Hsu, Shu-Ping Wang. Reshaping the tumor microenvironment: new application of tamoxifen in triple negative breast cancer immunomodulation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5953.