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Nitric oxide short-circuits interleukin-12-mediated tumor regression

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Abstract

Interleukin-12 (IL-12) can promote tumor regression via activation of multiple lymphocytic and myelocytic effectors. Whereas the cytotoxic mechanisms employed by T/NK/NKT cells in IL-12-mediated tumor kill are well defined, the antitumor role of macrophage-produced cytotoxic metabolites has been more controversial. To this end, we investigated the specific role of nitric oxide (NO), a major macrophage effector molecule, in post-IL-12 tumor regression. Analysis of tumors following a single intratumoral injection of slow-release IL-12 microspheres showed an IFNγ-dependent sevenfold increase in inducible nitric oxide synthase (iNOS) expression within 48 h. Flow cytometric analysis of tumor-resident leukocytes and in vivo depletion studies identified CD11b+ F4/80+ Gr1lo macrophages as the primary source of iNOS. Blocking of post-therapy iNOS activity with N-nitro-l-arginine methyl ester (L-NAME) dramatically enhanced tumor suppression revealing the inhibitory effect of NO on IL-12-driven antitumor immunity. Superior tumor regression in mice receiving combination treatment was associated with enhanced survival and proliferation of activated tumor-resident CD8+ T-effector/memory cells (Tem). These findings demonstrate that macrophage-produced NO negatively regulates the antitumor activity of IL-12 via its detrimental effects on CD8+ T cells and identify L-NAME as a potent adjuvant in IL-12 therapy of cancer.

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Acknowledgments

This work was supported by NIH/NCI grant R01-CA100656 (NKE) and DOD Grant BC0966372 (MOK).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, 138 Farber Hall, 3435 Main Street, Buffalo, NY, 14214, USA

    Nejat K. Egilmez, Jamie L. Harden, Lauren P. Virtuoso & Mehmet O. Kilinc

  2. Department of Pathology, University Hospital, 8091, Zürich, Switzerland

    Reto A. Schwendener

Authors
  1. Nejat K. Egilmez
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  2. Jamie L. Harden
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  3. Lauren P. Virtuoso
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  4. Reto A. Schwendener
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  5. Mehmet O. Kilinc
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Correspondence to Nejat K. Egilmez or Mehmet O. Kilinc.

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Egilmez, N.K., Harden, J.L., Virtuoso, L.P. et al. Nitric oxide short-circuits interleukin-12-mediated tumor regression. Cancer Immunol Immunother 60, 839–845 (2011). https://doi.org/10.1007/s00262-011-0998-2

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  • DOI: https://doi.org/10.1007/s00262-011-0998-2

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