In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5311-5311
Abstract:
Conditions that inhibit IFN-induced signal transduction and gene transcription can dampen the host immune system and its ability to recognize and eliminate tumors leading to impaired immunoediting. We hypothesized that in the setting of cancer, myeloid-derived suppressor cells (MDSC) could impair the responsiveness of immune effector cells to interferons. We used the murine adenocarcinoma cell line C26 which induces MDSC generation when implanted in C2DF1 mice. C26-bearing mice had significantly elevated levels of GR1+CD11b+ MDSC (p & lt;0.0001) and plasma IL-6 as compared to controls (p & lt;0.0001). The ability of IFNa or IFNy to stimulate phosphorylation of the STAT1 transcription factor (P-STAT1, a direct measure of IFN action) was measured by intracellular flow cytometry. Induction of P-STAT1 following a 15 minute stimulation of splenocytes with IFNa (102-104 U/mL) was significantly reduced in C26-bearing mice (Mean P-STAT1 = 18.8; Range = 4.0 - 33.4) as compared to control mice (Mean P-STAT1 = 37.9; Range = 27.0 - 50.0; p & lt;0.0001). A similar decrease in P-STAT1 in splenocytes of C26-bearing mice was observed following IFNy stimulation (1 ng/mL; 15 min; p=0.002). This decrease in IFN responsiveness was also observed in cells derived from inguinal lymph nodes following IFN-stimulation. The level of IFNa induced P-STAT1 was inversely correlated with the plasma IL-6 levels (Pearson correlation = −0.635; p=0.019). However, direct exogenous treatment of mice with IL-6 did not decrease splenic IFN response. In vitro co-culture experiments revealed that MDSC inhibited IFN-responsiveness of splenocytes from normal mice. Reduction of MDSC with either gemcitabine or anti-GR1 antibody treatment restored IFN responsiveness in splenocytes from C26-bearing mice as compared to tumor-bearing mice treated with vehicle or isotype control antibody. Spleens from C26-bearing animals displayed elevated levels of iNOS protein and nitric oxide (NO). The elevation in NO in C26-bearing mice was associated with increased levels of nitration on STAT1. In vitro treatment of splenocytes with a nitric oxide donor led to a decreased STAT1 IFN response. Taken together, these data suggest a novel link between MDSC and a decreased molecular response of the immune effectors responsible for promoting functional anti-tumor responses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5311.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-5311
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
