Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy

• Published in: The Journal of experimental medicine Vol. 207; no. 11; pp. 2455 - 2467
• Main Authors: Weiss, Jonathan M, Ridnour, Lisa A, Back, Tim, Hussain, S Perwez, He, Peijun, Maciag, Anna E, Keefer, Larry K, Murphy, William J, Harris, Curtis C, Wink, David A, Wiltrout, Robert H
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 25.10.2010
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antineoplastic Agents - pharmacology; Cadherins - immunology; Cadherins - metabolism; Carcinoma, Renal Cell - enzymology; Carcinoma, Renal Cell - immunology; Carcinoma, Renal Cell - pathology; Carcinoma, Renal Cell - therapy; CD40 Antigens - antagonists & inhibitors; CD40 Antigens - immunology; CD40 Antigens - metabolism; Enzyme Activation - drug effects; Enzyme Activation - immunology; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Immunotherapy; Interferon-gamma - biosynthesis; Interferon-gamma - immunology; Interleukin-2 - pharmacology; Macrophages - enzymology; Macrophages - immunology; Matrix Metalloproteinase 9 - biosynthesis; Matrix Metalloproteinase 9 - immunology; Mice; Mice, Inbred BALB C; Mice, Knockout; Neoplasm Metastasis; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase Type II - biosynthesis; Nitric Oxide Synthase Type II - immunology; Tissue Inhibitor of Metalloproteinase-1 - biosynthesis; Tissue Inhibitor of Metalloproteinase-1 - immunology
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20100670

Using an orthotopic model of renal cell carcinoma, we showed previously that IL-2/anti-CD40 immunotherapy resulted in synergistic anti-tumor responses, whereas IL-2 or α-CD40 alone mediated partial transient anti-tumor effects. We now show that treatment of tumor-bearing mice with IL-2/α-CD40, but not IL-2 or α-CD40, induced significant nitric oxide synthase (NOS) 2 expression in tumor-associated macrophages. In control-treated mice (low NO), NOS2 inhibition reduced tumor burden. However, during immunotherapy (high NO), NOS2 inhibition or macrophage depletion reversed the ability of IL-2/α-CD40 treatment to reduce lung metastases but had no effect on primary tumor burden. Furthermore, IL-2/α-CD40 induced the IFN-γ- and NO-dependent decrease in matrix metalloproteinase (MMP) expression and activity, concomitant with increases in tissue inhibitor of metalloproteinase (TIMP) 1 and E-cadherin expression within tumors. Finally, treatment of tumor-bearing mice with the NO donor JS-K significantly reduced metastases. These data differentiate the mechanism for primary anti-tumor effects of IL-2/α-CD40 immunotherapy, which are independent of NO, from the NO-dependent inhibition of metastases. Furthermore, reduced MMP9 activity implicates M1-polarized macrophages within the tumor microenvironment as critical components of therapeutic response. Our data demonstrate the mechanistic basis for IL-2/α-CD40-mediated control of metastases and suggest that the context-dependent application of NO donors may hold promise for prevention of metastatic disease.