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A Novel Role of Metalloproteinase in Cancer-mediated Immunosuppression¹

Departments of Obstetrics and Gynecology [B-C. S., H-N. H., S-C. H.], Pathology [H-C. L., S-M. H.], and Graduate Institute of Immunology [H-N. H., S-M. H., R-H. L.], National Taiwan University College of Medicine, Taipei, Taiwan, 100

Depressed immune responses have been observed frequently in cancer patients. In a variety of human malignancies, the expression of interleukin-2 receptor (IL-2R) on activated tumor-infiltrating lymphocytes was down-regulated. Because IL-2R 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-2R, a coculture model of in vitro mixed autologous lymphocytes and tumor cells was established. Kinetic analysis showed that cervical cancer cells down-regulated IL-2R expression on encountered T cells. The amount of IL-2R 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-2R expression on encountered T cells. By using protease inhibition assays we demonstrated that tissue inhibitors of metalloproteinase abrogated the cancer-mediated IL-2R 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-2R 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.

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