CD4 and nonpapillary renal cell carcinoma: The down-regulation of MHC class I and II in extended opioid-exposed ccRCC tumors suggests a decrease in the immunogenic signals of antigen-presenting cells to activate CD4+ T cells, which may lead to a decrease in the production of IL-2 and IFNγ and a reduced activation of cytotoxic CD8+ T cells/macrophages in opioid-exposed tumors (Figure 6).