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. 2008 Nov 4;105(44):17073-8.
doi: 10.1073/pnas.0806173105. Epub 2008 Oct 24.

Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase

Alexander J Muller  1 , Madhav D Sharma, Phillip R Chandler, James B Duhadaway, Mary E Everhart, Burles A Johnson 3rd, David J Kahler, Jeanene Pihkala, Alejandro Peralta Soler, David H Munn, George C Prendergast, Andrew L Mellor
Affiliations

Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase

V体育ios版 - Alexander J Muller et al. Proc Natl Acad Sci U S A. .

Abstract

Topical application of phorbol myristate acetate (PMA) elicits intense local inflammation that facilitates outgrowth of premalignant lesions in skin after carcinogen exposure. The inflammatory response to PMA treatment activates immune stimulatory mechanisms. However, we show here that PMA exposure also induces plasmacytoid dendritic cells (pDCs) in local draining lymph nodes (dLNs) to express indoleamine 2,3 dioxygenase (IDO), which confers T cell suppressor activity on pDCs. The induced IDO-mediated inhibitory activity in this subset of pDCs was potent, dominantly suppressing the T cell stimulatory activity of other DCs that comprise the major fraction of dLN DCs. IDO induction in pDCs depended on inflammatory signaling by means of IFN type I and II receptors, the TLR/IL-1 signaling adaptor MyD88, and on cellular stress responses to amino acid withdrawal by means of the integrated stress response kinase GCN2. Consistent with the hypothesis that T cell suppressive, IDO(+) pDCs elicited by PMA exposure create local immune privilege that favors tumor development, IDO-deficient mice exhibited a robust tumor-resistant phenotype in the standard DMBA/PMA 2-stage carcinogenesis model of skin papilloma formation. Thus, IDO is a key immunosuppressive factor that facilitates tumor progression in this setting of chronic inflammation driven by repeated topical PMA exposure VSports手机版. .

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Conflict of interest statement

Conflict of interest statement: A. J. M. , D. H. M. , G. C. P. , and A. L V体育安卓版. M. are members of the Scientific Advisory Board for NewLink Genetics Inc. and receive consulting income from this source.

Figures

Fig. 1.
Fig. 1.
Topical PMA treatment stimulates IDO1 expression in dLNs. (A–C) Inguinal dLN sections from PMA-treated (A and B) and untreated B6 (C) mice were stained with anti-IDO Ab (red chromogen; magnifications, 100x in A and C, 400x in B). (D) Kynurenine present in homogenized dLNs from PMA and acetone (vehicle) treated BALB/c (WT) and IDO1-KO mice was measured by LC/MS/MS as described in Methods.
Fig. 2.
Fig. 2.
PMA treatment stimulates dLN pDCs to acquire potent T cell suppressor activity by means of IDO. (A) An example of the sorting criteria used to select dLN pDCs (CD11c+B220+) and mDCs (CD11c+B220NEG) from PMA-treated mice. (B) Sorted dLN pDCs or mDCs were added separately (or as pDC:mDC mixtures in the proportions shown) to cultures containing OT-1 responder T cells and cognate OVA peptide with or without D-1MT. Thymidine incorporation was measured after 72 h. Dotted arrows indicate significant suppression (P < 0.05) due to IDO activity. Data shown is from quadruplicate cultures (error bars, SD = 1), and are representative of 5 (pDCs, mDCs) or 2 (pDC:mDC mixtures) separate experiments.
Fig. 3.
Fig. 3.
Genetic and pharmacologic ablation of IDO blocks induction of pDC suppressor activity. PMA was applied to skin of IDO1-KO (A); B6 (WT) mice (B–D). Some mice were also given (C) IDO inhibitor (D-1MT, 2 mg/mL) and sweetener or (D) sweetener only in drinking water starting 2 days before the first PMA treatment (day 0) until 2 days after the third PMA treatment (day 9). As before, sorted LN pDCs were incubated with OT-1 responders and OVA peptide with or without D-1MT. Data are representative of at least 2 experiments. Data shows significant suppression (B and D, P < 0.05) or no significant suppression (A and C, P > 0.05) and triplicate (or more) cultures were analyzed.
Fig. 4.
Fig. 4.
Inflammatory and cell stress signals induce pDCs to acquire suppressor activity by means of IDO. PMA was applied to the skin of (A) IFNAR-KO, (B) IFNRα-KO, (C) MyD88-KO (D), GCN2-KO mice, or WT (BALB/c, 129SvJ) mice. Sorted dLN pDCs from PMA-treated mice were cultured with responder DO11.10 (A and E) or OT-1 (B–D and F) T cells and cognate (OVA) peptide, and proliferation was assessed with or without D-1MT. No significant suppression by means of IDO was detected in KO mice (A–D, P > 0.05), whereas significant suppression was detected in WT mice (E and F, P < 0.05). Triplicate (or more) cultures were analyzed and experiments were repeated 2 or more times.
Fig. 5.
Fig. 5.
IDO is crucial for PMA-driven skin carcinogenesis. B6 strain WT (n = 10) and IDO1-KO (n = 8) mice received a single topical application of 400 nM DMBA at week 0, followed by twice weekly applications of 10 μg of PMA from week 1 until week 20. Mice were evaluated for papillomas twice a week. (Upper) The numbers of papillomas per mouse over time plotted as mean values for each group ± SE. Significance (P < 0.0004) was determined a nonparametric 2-tailed Mann–Whitney test. (Lower) Number of mice remaining papilloma-free over time plotted as a survival curve. Significance (P < 0.0005) was determined by using a 2-group log-rank test (equivalent to the Mantel–Haenszel test).
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