The role of CX3CL1 in the targeted immunotherapy of HER2-positive breast cancer

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A major mechanism of action of monoclonal antibodies in cancer therapy is the labeling of tumor cells for the attack by natural killer (NK) cells, a process called antibody-dependent cell-mediated cytotoxicity (ADCC). Such a mode of action has been documented for the HER2-specific antibody trastuzumab. A fundamental requirement for the success of such therapies is a sufficient infiltration of immune effector cells into the tumor and a close binding of these cells to the tumor cells.The soluble chemokine CX3CL1 secreted by tumor cells is capable of recruiting CX3CR1-expressing NK cells into solid cancers thereby improving ADCC. However, initially it is synthesized as a membrane-bound form which function in cancer has not been elucidated yet. It is conceivable that this membrane-bound form further enhances immune responses due to a closer binding of immune cells to the tumor cells. Release of the soluble form is mediated mainly by the two proteases ADAM10 and ADAM17 through cleavage of the membrane-bound form. It is yet unclear which effect both forms of CX3CL1 have on the CX3CR1 receptor on tumor cells. In the present project we want to elucidate the function of both CX3CL1 forms using HER2-positive breast cancer as a model disease.In a first step we want to investigate the regulation of both forms of CX3CL1 and their impact on NK cell-mediated ADCC of trastuzumab-treated HER2-positive breast cancer cell lines in vitro (subproject 1). In addition, we study the effect of CX3CL1 on a trastuzumab therapy in a humanized tumor mouse model of HER2-positive breast cancer in vivo (subproject 2). In the third subproject we want to substantiate the results obtained in the first two subprojects through a retrospective analysis of HER2-positive breast cancer samples. Herein we investigate the expression of the proteins involved (CX3CL1, CX3CR1, ADAM10 and ADAM17) and correlate them with the clinical follow-up data as well as with the lymphocytic infiltrate (subproject 3).The results are intended to provide a basis for a pharmacological regulation of CX3CL1 eventually improving immune intervention in breast cancer.