The greatest hurdle in cancer treatment is the metastasis of primary tumors to distant organs. Our knowledge on how different immune cells, in the absence of exogenous stimulation, prevent tumor metastasis in distant organs is poorly understood. Using a highly metastatic murine lung B16 melanoma cell line BL6-10, we employed naive mice that genetically lack CD4(+) or CD8(+) T cells, or are depleted of dendritic cells (DCs) or natural killer (NK) cells to understand the relative importance of these cells in metastasis prevention. Irrespective of the presence of naïve CD4(+) T, CD8(+) T, DCs, or NK cells, lungs, which act as primary site of predilection for B16 melanoma, readily developed numerous lung BL6-10 melanoma colonies. However, their absence led to B16 melanoma metastasis in variable proportions to distant organs, particularly livers, kidneys, adrenals, ovaries, and hearts. NK cells mediate prevention of BL6-10 metastasis to various organs, especially to livers. Mechanistically, CD40L signaling, a critical factor required for DC licensing and CD8(+) cytotoxic T lymphocyte (CTL) responses, was required for CD4(+) T cell-mediated prevention of systemic BL6-10 metastasis. These results suggest that the composition and functions of different immune cells in distant tissue microenvironments (distant organs other than primary sites of predilection) robustly mediate natural resistance against melanoma metastasis. Thus, harnessing these immune cells' responses in immunotherapeutics would considerably limit organ metastasis.
Keywords: B16 melanoma; innate and adoptive immune cells; natural resistance; systemic metastasis.