TIMP-2 targets tumor-associated myeloid suppressor cells with effects in cancer immune dysfunction and angiogenesis.
Angiogenesis and inflammation are important therapeutic targets in non-small cell lung cancer (NSCLC). It is well known that proteolysis mediated by matrix metalloproteinases (MMPs) promotes angiogenesis and inflammation in the tumor microenvironment. Here, the effects of the MMP inhibitor TIMP-2 on NSCLC inflammation and angiogenesis were evaluated in TIMP-2-deficient (timp2-/-) mice injected subcutaneously (SC) with Lewis lung carcinoma cells and compared with the effects on tumors in wild-type mice. TIMP-2-deficient mice demonstrated increased tumor growth, enhanced expression of angiogenic marker αvβ3 in tumor and endothelial cells, and significantly higher serum vascular endothelial growth factor-A levels. Tumor-bearing timp2-/- mice showed a significant number of inflammatory cells in their tumors, upregulation of inflammation mediators, nuclear factor-kappaB, and Annexin A1, as well as higher levels of serum interleukin (IL)-6. Phenotypic analysis revealed an increase in myeloid-derived suppressor cell (MDSC) cells (CD11b+ and Gr-1+) that coexpressed vascular-endothelial-growth factor receptor 1 (VEGF-R1) and elevated MMP activation present in tumors and spleens from timp2-/- mice. Furthermore, TIMP-2-deficient tumors upregulated expression of the immunosuppressing genes controlling MDSC growth, IL-10, IL-13, IL-11, and chemokine ligand (CCL-5/RANTES), and decreased interferon-γ and increased CD40L. Moreover, forced TIMP-2 expression in human lung adenocarcinoma A-549 resulted in a significant reduction of MDSCs recruited into tumors, as well as suppression of angiogenesis and tumor growth. The increase in MDSCs has been linked to cancer immunosuppression and angiogenesis. Therefore, this study supports TIMP-2 as a negative regulator of MDSCs with important implications for the immunotherapy and/or antiangiogenic treatment of NSCLC.
*Extracellular Matrix Pathology Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. guedezl@mail.nih.gov
Liliana
L
Guedez
Sandra
S
Jensen-Taubman
Dimitra
D
Bourboulia
Clifford J
CJ
Kwityn
Beiyang
B
Wei
John
J
Caterina
William G
WG
Stetler-Stevenson
D000818:Animals; D017305:Annexin A1 / Q000096:biosynthesis; D019013:CD40 Antigens / Q000096:biosynthesis; D018827:Carcinoma, Lewis Lung; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018946:Chemokine CCL5 / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D017370:Interleukin-11 / Q000096:biosynthesis; D018793:Interleukin-13 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000097:blood; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D045726:Metalloproteases / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D022423:Myeloid Cells / Q000378:metabolism*; D016328:NF-kappa B / Q000096:biosynthesis; D009389:Neovascularization, Pathologic; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
D017305:Annexin A1; D019013:CD40 Antigens; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D017370:Interleukin-11; D018793:Interleukin-13; D015850:Interleukin-6; D016328:NF-kappa B; C573274:annexin A1, mouse; D019716:Tissue Inhibitor of Metalloproteinase-2; D016753:Interleukin-10; D007371:Interferon-gamma; D040281:Vascular Endothelial Growth Factor Receptor-1; D045726:Metalloproteases