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 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.
Sheu
B C
BC
Department of Obstetrics and Gynecology, National Taiwan University College of Medicine, Taipei.
Hsu
S M
SM
Ho
H N
HN
Lien
H C
HC
Huang
S C
SC
Lin
R H
RH
D002584:Cervix Uteri / Q000166:cytology; D018920:Coculture Techniques; D015536:Down-Regulation; D004847:Epithelial Cells; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007376:Interleukin-2; D007527:Isoenzymes / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D017154:Stromal Cells; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology; D014158:Transcription, Genetic; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000276:immunology*
D007376:Interleukin-2; D007527:Isoenzymes; D015375:Receptors, Interleukin-2; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D008666:Metalloendopeptidases