Immune checkpoint inhibitors have shown success in treating a subset of patients with certain late-stage cancers. However, these treatments fail in many other patients, due to mechanisms that have yet to be fully characterized. The process of T cell exhaustion, by which T cells become dysfunctional in response to extended exposure to antigen, has been implicated in immunotherapy resistance. We constructed an analysis framework to first rank human skin tumor samples by degree of exhaustion in tumor-infiltrating CD8 T cells and then identify immune cell type-specific gene regulatory network patterns significantly associated with T cell exhaustion.