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

Jonathan M. Weiss, Lisa A. Ridnour, Tim Back, S. Perwez Hussain, Peijun He, Anna E. Maciag, Larry K. Keefer, William J Murphy, Curtis C. Harris, David A. Wink, Robert H. Wiltrout

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2455-2467
Number of pages13
JournalJournal of Experimental Medicine
Issue number11
StatePublished - Oct 25 2010

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy


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