A novel role of metalloproteinase in cancer-mediated immunosuppression

• Published in: Cancer research (Chicago, Ill.) Vol. 61; no. 1; pp. 237 - 242
• Main Authors: SHEU, Bor-Ching, HSU, Su-Ming, HO, Hong-Nerng, LIEN, Huang-Chun, HUANG, Su-Cheng, LIN, Rong-Hwa
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 2001
• Subjects: Biological and medical sciences; Cervix Uteri - cytology; Coculture Techniques; Down-Regulation; Epithelial Cells; Female; Gene Expression Regulation, Neoplastic; Host-tumor relations. Immunology. Biological markers; Humans; Immune Tolerance - immunology; Interleukin-2; Isoenzymes - biosynthesis; Lymphocyte Activation - immunology; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Medical sciences; Metalloendopeptidases - antagonists & inhibitors; Metalloendopeptidases - immunology; Metalloendopeptidases - metabolism; Neurology; Receptors, Interleukin-2 - biosynthesis; Receptors, Interleukin-2 - immunology; Receptors, Interleukin-2 - metabolism; Stromal Cells; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tissue Inhibitor of Metalloproteinase-1 - pharmacology; Tissue Inhibitor of Metalloproteinase-2 - pharmacology; Transcription, Genetic; Tumors; Tumors of the nervous system. Phacomatoses; Uterine Cervical Neoplasms - enzymology; Uterine Cervical Neoplasms - immunology; Human; Enzyme; Metalloendopeptidases; Cytotoxicity; Tumor infiltrating lymphocyte; Autologous system; Uterine cervix; Malignant tumor; In vitro; Gelatinase B; Female genital diseases; Gelatinase A; Peptidases; Immunosuppression; Monolayer culture; Interleukin 2; T-Lymphocyte; Hydrolases; Mechanism of action; Uterine cervix diseases; Tumor cell; Interstitial collagenase; Biological receptor
• ISSN: 0008-5472; 1538-7445

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-2R alpha expression on encountered T cells. By using protease inhibition assays we demonstrated that tissue inhibitors of metalloproteinase abrogated the cancer-mediated IL-2R alpha 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.