Endogenous mu-opioid peptides modulate immune response towards malignant melanoma

Opioids exert major effects not only in the central nervous system but also in immune responses. We investigated the effects of mu-opioid peptides, secreted by tumor cells, on anti-tumor immune responses. For this purpose, tumor growth was studied in wild-type and mu-opioid receptor-deficient (MOR-/-) mice injected with B16 melanoma cells. The ability of these cells to produce opioids was studied by Western blots in vitro. Finally, biopsy material from human melanomas was investigated by immunohistochemistry for ss endorphin expression. Injection of B16 melanoma cells, producing endogenous ss endorphin, in the flank of MOR-/- mice revealed a profound reduction in tumor growth, paralleled by a significantly higher infiltration of immune cells into the tumors, when compared to tumor growth after injection of B16 melanoma cells into wild-type mice. Opioids present in B16 cell supernatant significantly reduced the proliferation of normal but not MOR-/- leucocytes. Immunohistochemical analyses of biopsies from human melanoma tissues showed a positive correlation between expression of ss endorphin and tumor progression. Our data provide evidence that mu-opioid peptides may play a major role in cancer progression by modulating immune response. This finding may have implications for the future optimization of immunointerventions for cancer.