Improvement of NK cell-infusion therapy for metastatic breast cancer by targeting tumour-associated macrophages

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Breast cancer is one of the leading causes of cancer death in women. Although most cancer in the breast (primary tumours) can be resected surgically, it often spreads to the different part of the body such as the bone and lung (metastatic tumours) and this is responsible for the high mortality of the disease. Since existing therapies are not sufficient to prolong survival of patients with metastatic breast cancer, novel approaches are required to improve outcome. An emerging therapeutic strategy is the infusion of immune cells called natural killer (NK) cell that can directly kill certain types of cancer cells. Clinical and pre-clinical studies have shown that infusion of NK cells exerts modest therapeutic effects in breast cancer patients without adverse side effects. However, several reports show that NK cells cannot exhibit full anti-tumour ability in the environment of the tumour, suggesting that elimination of such a suppressive environment is needed to use the NK cells as a therapeutic tool. Recent studies suggest that other types of immune cells called tumour-associated macrophages (TAMs) can suppress NK cell functions in the primary tumours. However, their roles in the metastatic tumours are largely unknown. Using animal models of metastatic breast cancer, I have reported that TAMs are one of the most abundant cell types in the environment of metastatic tumours, and their accumulation helps cancer cells to establish the lethal metastatic tumours. Furthermore, my recent studies suggest that the TAMs in the metastatic tumours can suppress NK cell-induced tumour cell death in vitro. We have also found that macrophages acquire NK cell suppressive functions when they are stimulated with conditioned media that are harvested from cultured cancer cells and thus include several factors secreted by cancer cells. I thus predict that the TAMs in the metastatic tumor environment are educated by cancer cells to prevent therapeutic effects of the infused NK cells on the metastatic breast cancer. The overarching ambition of my project is to improve efficacy of the NK cell-based therapy against metastatic breast cancer by blocking functions of TAMs. To achieve this ultimate goal, this proposal has three specific aims. The first aim is to define how TAMs suppress NK cell functions. We will isolate TAMs from murine metastatic tumors, and investigate their effects on NK cell movement, activation, killing factor expression, and tumor killing activity using in vitro assays established by us. The second aim is to identify therapeutic targets that can potentiate human NK cell efficacy. We will identify candidate factors that are highly expressed in human macrophages educated by cancer cells, and assess whether ablation of these factors prevent the macrophage mediated suppression of the NK cell functions. We will also define the cancer cell-derived factors that educate human macrophages to be NK suppressive cells. The third aim is to develop clinically relevant models for validation of the therapeutic targets and further drug discovery. We have established a protocol to differentiate human induced pluripotent stem cell (iPSC) into mature macrophages and NK cells. Using these cells, we will develop our in vitro assay into a more clinically relevant model. We will also establish a mouse model by which we can assess therapeutic effects of human NK cell infusion combined with blockade of identified therapeutic targets on the metastasis formation of human breast cancer cells. I believe that this research will show us the essential factors for TAMs to suppress NK cell functions, which will lead us to develop novel approaches to improve efficacy of NK cell-based therapy for metastatic diseases. The funding from this award would allow me to expand my research group, enhance my independence, develop further collaborations, and thereby identify new strategies that will potentially prolong survival of metastatic breast cancer patients.