A novel role of metalloproteinase in cancer-mediated immunosuppression

Depressed immune responses have been observed frequently in cancer patients. In a variety of human malignancies, the expression of interleukin-2 receptor α (IL-2Rα) on activated tumor-infiltrating lymphocytes was down-regulated. Because IL-2Rα plays a pivotal role in the development and propagation of functional T cells, its depressed expression may result in poor function of tumor-reactive cytotoxic lymphocytes. For elucidating the mechanism responsible for down-regulation of IL-2Rα, a coculture model of in vitro mixed autologous lymphocytes and tumor cells was established. Kinetic analysis showed that cervical cancer cells downregulated IL-2Rα expression on encountered T cells. The amount of IL-2Rα mRNA in tumor-infiltrating lymphocytes-derived CD8 ⁺ T cells was compatible with that in the corresponding activated CD8 ⁺ T cells. Additional evidence showed that cervical cancer cells could induce the release of soluble IL-2Rα expression on encountered T cells. By using protease inhibition assays we demonstrated that tissue inhibitors of metalloproteinase abrogated the cancer-mediated IL-2Rα proteolytic process and restored the T-cell proliferation function. Immunohistochemical stainings further revealed prominent metalloproteinase (MMP) expressions, including MMP-1, MMP-2, and MMP-9, in cervical cancer tissues. Additional in vitro studies showed that MMP-9 mediates cleavage of IL-2Rα and down-regulates the proliferative capability of cancer-encountered T cells. Our findings suggest a new role of MMPs in tumor-mediated immunosuppression and provide a possible therapeutic potential for patients with cervical cancer.