|Title:||A Novel Role of Metalloproteinase in Cancer-Mediated Immunosuppression||Authors:||HUANG, SU-CHENG
|Keywords:||TUMOR-INFILTRATING LYMPHOCYTES;HUMAN CERVICAL-CARCINOMA;INTERLEUKIN-2 RECEPTOR;INHIBITOR BLOCKS;GELATINASE-B;CELLS||Issue Date:||2001||Journal Volume:||v.61||Journal Issue:||n.1||Start page/Pages:||237-242||Source:||CANCER RESEARCH||Abstract:||
Depressed immune responses have been observed frequently in cancer patients. In a variety of human malignancies, the expression of interleukin-2 receptor alpha (IL-2R alpha) on activated tumor-infiltrating lymphocytes was down-regulated. Because IL-2R alpha 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 alpha, 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 alpha expression on encountered T cells. The amount of IL-2R alpha 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-2Ra expression on encountered T cells. By using protease inhibition assays we demonstrated that tissue inhibitors of metalloproteinase abrogated the cancer-mediated IL-2Ra 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 alpha 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.
|Appears in Collections:||醫學系|
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