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

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Abstract

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
Volume207
Issue number11
DOIs
StatePublished - Oct 25 2010

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Immunotherapy
Interleukin-2
Nitric Oxide
Macrophages
Neoplasm Metastasis
Neoplasms
Tumor Burden
Tissue Inhibitor of Metalloproteinase-1
Tumor Microenvironment
Cadherins
Therapeutics
Matrix Metalloproteinases
Renal Cell Carcinoma
Nitric Oxide Synthase
Lung

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Weiss, J. M., Ridnour, L. A., Back, T., Hussain, S. P., He, P., Maciag, A. E., ... Wiltrout, R. H. (2010). Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy. Journal of Experimental Medicine, 207(11), 2455-2467. https://doi.org/10.1084/jem.20100670

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

In: Journal of Experimental Medicine, Vol. 207, No. 11, 25.10.2010, p. 2455-2467.

Research output: Contribution to journalArticle

Weiss, JM, Ridnour, LA, Back, T, Hussain, SP, He, P, Maciag, AE, Keefer, LK, Murphy, WJ, Harris, CC, Wink, DA & Wiltrout, RH 2010, 'Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy', Journal of Experimental Medicine, vol. 207, no. 11, pp. 2455-2467. https://doi.org/10.1084/jem.20100670
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. / Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy. In: Journal of Experimental Medicine. 2010 ; Vol. 207, No. 11. pp. 2455-2467.
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AU - He, Peijun

AU - Maciag, Anna E.

AU - Keefer, Larry K.

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