靶向肿瘤免疫微环境以提高化疗药物对乳腺癌的疗效

Breast cancer (BC) is the most common cancer worldwide and the second leading cause of cancer related death for women in the US. Despite significant advances in mechanistic exploration and therapeutic intervention, improving the overall survival rate (OS), treating metastatic breast cancer remains an urgent challenge. Estrogen, progesterone and human epidermal growth factor 2 (HER2) receptor triple negative BC (TNBC), for example, has a 5-year OS of 11% and a median OS of only 11 to 13 months. Due to the lack of a feasible target or biomarkers for targeted therapy, chemo agents serve as a limited therapeutic option for metastatic TNBC. Currently, clinical application of chemotherapy has been significantly limited by age-related and dosage-dependent cytotoxicity of chemo agents. While recent studies have suggested that the tumor immune microenvironment (TIME) plays an important role in chemoresistance, how to target the TIME to improve the efficacy of chemotherapy against TNBC has remained largely unknown. In this study, we characterized the immune cell profile in the TIME of BC and found that the expression level of the homeobox protein VentX, a transcription factor implicated in macrophage plasticity, is significantly downregulated in BC tumor associated macrophages (TAMs). We found that down-regulated VentX expression in BC-TAMs is associated with their pro-tumor M2-like phenotype and is accompanied by the increased population of immune suppressive T reg cells in the BC-TIME. We also demonstrated that ectopic expression of VentX in BC-TAMs converted its pro-tumor M2-like phenotype into an anti-tumor M1 phenotype. Using an ex-vivo TIME enabling model system (TIME-EMS) developed in the lab, we showed that elevated expression of VentX in BC-TAMs led to transformation of the BC-TIME from an immune suppressive state into an immune activated state. Using the TIME-EMS models of BC, we explored the effects of chemo agents on cancer cells in BC-TIME. We discovered that conversion of BC-TIME from an immune suppressive state into an immune activated state drastically increased the sensitivity of cancer cells to the chemotherapeutic agent paclitaxel. Besides TNBC, we showed that reversal of immune suppression of BC-TIME also improves chemosensitivity of paclitaxel on other sub-groups of BC. We also demonstrated that elevated expression of VentX in BC-TAMs did not increase the cytotoxicity of paclitaxel on normal breast epithelial cells. In summary, our work demonstrates the utility of the TIME-EMS models as an ex-vivo model system to explore treatment options for BC in the context of the TIME. Our results suggest that VentX may serve as a potential therapeutic target to improve the efficacy of chemo agents against BC and improve prognosis of TNBC patients who have limited therapeutic options.