Immunotherapies against cancer continue to improve, but many cancers show primary or secondary resistance. Novel research strategies are necessary to reach a comprehensive understanding of the underlying mechanisms. There is increasing evidence that T cells themselves provoke immune escape of cancer cells. In this chapter we describe a co-culture system to analyze the dynamic interplay between T cells and cancer cells. Using human melanoma cell lines and T cell clones, we obtained reproducible and comparable results despite the high heterogeneity of tumor cells. We show the feasibility of differential protein and gene expression analysis of melanoma cells isolated from our culture system. Thus, the system allows quantifying broadly the differential gene expression in melanoma cells upon interaction with T cells, revealing immune-related reactions in cancer cells. Many parts of this chapter were previously published in an original paper and are reproduced here for this book.