Mast cells impair the development of protective anti-tumor immunity

Mast cells have emerged as critical intermediaries in the regulation of peripheral tolerance. Their presence in many precancerous lesions and tumors is associated with a poor prognosis, suggesting mast cells may promote an immunosuppressive tumor microenvironment and impede the development of protective anti-tumor immunity. The studies presented herein investigate how mast cells influence tumor-specific T cell responses. Male MB49 tumor cells, expressing HY antigens, induce anti-tumor IFN-gamma(+) T cell responses in female mice. However, normal female mice cannot control progressive MB49 tumor growth. In contrast, mast cell-deficient c-Kit(Wsh) (W-sh) female mice controlled tumor growth and exhibited enhanced survival. The role of mast cells in curtailing the development of protective immunity was shown by increased mortality in mast cell-reconstituted W-sh mice with tumors. Confirmation of enhanced immunity in female W-sh mice was provided by (1) higher frequency of tumor-specific IFN-gamma(+) CD8(+) T cells in tumor-draining lymph nodes compared with WT females and (2) significantly increased ratios of intratumoral CD4(+) and CD8(+) T effector cells relative to tumor cells in W-sh mice compared to WT. These studies are the first to reveal that mast cells impair both regional adaptive immune responses and responses within the tumor microenvironment to diminish protective anti-tumor immunity.