Melanocytic nevi are benign proliferations of pigment cells that can occasionally develop into
melanomas. There is a significant correlation between increased
nevus numbers and
melanoma development. Our previous reports revealed that
7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induced
dysplastic nevi in C3H/HeN mice, with a potential to transform into
melanomas. To understand the immune mechanisms behind this transformation, we applied increasing DMBA doses followed by TPA to the skin of C3H/HeN mice. We observed that increased doses of DMBA correlated well with increased numbers of
nevi. The increased DMBA dose induced diminished immune responses and promoted the expansion of regulatory T cells (Treg) that resulted in increased
IL10 and reduced IFNγ levels. Mice with increased
nevus numbers had loss of p16 expression. These mice had increased migration of melanocytic cells to lymph nodes (LN) and a greater percent of LNs produced immortalized melanocytic cell lines. DMBA-induced immunosuppression was lost in CD4-knockout (KO) mice. Lymphocytes in the CD4KO mice produced less
IL10 than CD8KO mice. Furthermore, CD4KO mice had significantly reduced
nevus numbers and size compared with wild-type and CD8KO mice. These results suggest that Tregs play a vital role in the incidence of
nevi and their progression to
melanoma.Prevention Relevance: There has been little progress in developing novel strategies for preventing premalignant
dysplastic nevi from becoming
melanomas. In this study in mice, regulatory-T cells enhanced progression of benign
nevi to
malignant melanomas; and by inhibiting their activity,
melanomas could be retarded. The findings identify new possibilities for
melanoma prevention in high risk individuals.