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


Egilmez, N K; Harden, J L; Virtuoso, L P; Schwendener, R A; Kilinc, M O (2011). Nitric oxide short-circuits interleukin-12-mediated tumor regression. Cancer Immunology, Immunotherapy, 60(6):839-845.

Abstract

Interleukin-12 (IL-12) can promote tumor
regression via activation of multiple lymphocytic and myelocytic
eVectors. Whereas the cytotoxic mechanisms employed
by T/NK/NKT cells in IL-12-mediated tumor kill are well
deWned, the antitumor role of macrophage-produced cytotoxic
metabolites has been more controversial. To this end,
we investigated the speciWc role of nitric oxide (NO), a major
macrophage eVector molecule, in post-IL-12 tumor regression.
Analysis of tumors following a single intratumoral
injection of slow-release IL-12 microspheres showed an
IFN-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 identiWed 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 eVect 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-eVector/memory
cells (Tem). These Wndings demonstrate that macrophageproduced
NO negatively regulates the antitumor activity of
IL-12 via its detrimental eVects on CD8+ T cells and identify
L-NAME as a potent adjuvant in IL-12 therapy of cancer.

Abstract

Interleukin-12 (IL-12) can promote tumor
regression via activation of multiple lymphocytic and myelocytic
eVectors. Whereas the cytotoxic mechanisms employed
by T/NK/NKT cells in IL-12-mediated tumor kill are well
deWned, the antitumor role of macrophage-produced cytotoxic
metabolites has been more controversial. To this end,
we investigated the speciWc role of nitric oxide (NO), a major
macrophage eVector molecule, in post-IL-12 tumor regression.
Analysis of tumors following a single intratumoral
injection of slow-release IL-12 microspheres showed an
IFN-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 identiWed 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 eVect 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-eVector/memory
cells (Tem). These Wndings demonstrate that macrophageproduced
NO negatively regulates the antitumor activity of
IL-12 via its detrimental eVects on CD8+ T cells and identify
L-NAME as a potent adjuvant in IL-12 therapy of cancer.

Citations

10 citations in Web of Science®
13 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2011
Deposited On:16 Jun 2011 08:29
Last Modified:05 Apr 2016 14:56
Publisher:Springer
ISSN:0340-7004
Publisher DOI:https://doi.org/10.1007/s00262-011-0998-2
PubMed ID:21387108

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