Role of macrophage-mediated chemokine signals in efficacy of therapeutic modalities for metastatic outgrowth of breast cancer cells

Development of metastatic tumors dramatically reduces survival rate of breast cancer patients, thus suppression of metastatic tumor outgrowth is essential to prolong overall survival of patients. Metastatic breast cancer is primarily treated by cytotoxic agents such as Doxorubicin, but response to single treatment is restricted by resistance to the agent. An alternative strategy is immunotherapy utilizing cancer vaccines or immune-checkpoint inhibitors, although its application appears to be limited to tumors expressing specific antigens. Another option is adoptive transfer of NK cells, which is reported to be safe and have modest efficacy in metastatic breast cancer, whereas data suggest that NK cells cannot exhibit full cytotoxic capacity in the tumor microenvironment. Although resistance to these therapies can be caused by tumor cell intrinsic mechanisms, recent studies using primary tumor models suggest pivotal roles of tumor-associated macrophages (TAMs). Using metastatic breast cancer mouse models, we have reported that TAMs are recruited to the metastatic lung and interact with disseminating breast cancer cells via chemokine signals, which promotes metastatic tumor outgrowth.
The aim of this project is to test whether macrophage blockade by inhibiting these chemokine signals can improve efficacies of doxorubicin treatment and NK-cell-based immunotherapy.