NKG2D is an activating receptor for NK, NKT, CD8+, and γδ+ T cells, whose aberrant loss in cancer is a key mechanism of immune evasion. Soluble NKG2D ligands and growth factors, such as TGFβ1 emanating from tumors, are mechanisms for down-regulating NKG2D expression. Cancers thereby impair the capacity of lymphocytes to recognize and destroy them. In this study, we show that exosomes derived from cancer cells express ligands for NKG2D and express TGFβ1, and we investigate the impact of such exosomes on CD8+ T and NK cell NKG2D expression and on NKG2D-dependent functions. Exosomes produced by various cancer cell lines in vitro, or isolated from pleural effusions of mesothelioma patients triggered down-regulation of surface NKG2D expression by NK cells and CD8+ T cells. This decrease was rapid, sustained, and resulted from direct interactions between exosomes and NK cells or CD8+ T cells. Other markers (CD4, CD8, CD56, CD16, CD94, or CD69) remained unchanged, indicating the selectivity and nonactivatory nature of the response. Exosomal NKG2D ligands were partially responsible for this effect, as down-modulation of NKG2D was slightly attenuated in the presence of MICA-specific Ab. In contrast, TGFβ1-neutralizing Ab strongly abrogated NKG2D down-modulation, suggesting exosomally expressed TGFβ as the principal mechanism. Lymphocyte effector function was impaired by pretreatment with tumor exosomes, as these cells exhibited poor NKG2D-dependent production of IFN-γ and poor NKG2D-dependent killing function. This hyporesponsiveness was evident even in the presence of IL-15, a strong inducer of NKG2D. Our data show that NKG2D is a likely physiological target for exosome-mediated immune evasion in cancer.
Purpose Venous thromboembolism (VTE) is common in cancer patients. Evidence has suggested that low molecular weight heparin (LMWH) might improve survival in patients with cancer by preventing both VTE and the progression of metastases. No trial in a single cancer type has been powered to demonstrate a clinically significant survival difference. The aim of this trial was to investigate this question in patients with lung cancer. Patients and Methods We conducted a multicenter, open-label, randomized trial to evaluate the addition of a primary prophylactic dose of LMWH for 24 weeks to standard treatment in patients with newly diagnosed lung cancer of any stage and histology. The primary outcome was 1-year survival. Secondary outcomes included metastasis-free survival, VTE-free survival, toxicity, and quality of life. Results For this trial, 2,202 patients were randomly assigned to the two treatment arms over 4 years. The trial did not reach its intended number of events for the primary analysis (2,047 deaths), and data were analyzed after 2,013 deaths after discussion with the independent data monitoring committee. There was no evidence of a difference in overall or metastasis-free survival between the two arms (hazard ratio [HR], 1.01; 95% CI, 0.93 to 1.10; P = .814; and HR, 0.99; 95% CI, 0.91 to 1.08; P = .864, respectively). There was a reduction in the risk of VTE from 9.7% to 5.5% (HR, 0.57; 95% CI, 0.42 to 0.79; P = .001) in the LMWH arm and no difference in major bleeding events but evidence of an increase in the composite of major and clinically relevant nonmajor bleeding in the LMWH arm. Conclusion LMWH did not improve overall survival in the patients with lung cancer in this trial. A significant reduction in VTE is associated with an increase in clinically relevant nonmajor bleeding. Strategies to target those at greatest risk of VTE are warranted.
Nitric oxide (NO) can be detected in exhaled gas in human subjects. It is produced by nitric oxide synthase (NOS) and is rapidly metabolized to nitrite and nitrate (NO2/NO3). Exhaled NO is reported to be elevated in patients with asthma, bronchiectasis, or upper respiratory tract infection. Recent reports have shown no increase of exhaled NO in stable cystic fibrosis (CF). We hypothesized that NOS activity is increased in patients with acute pulmonary exacerbation of CF. We therefore measured exhaled NO and sputum NO2/NO3 in three subject categories: patients with acute pulmonary exacerbation of CF, patients with stable CF, and healthy control subjects. Mean +/- SD exhaled NO was significantly higher in control subjects (8.8 +/- 4.9 ppb) than in both acute (3.8 +/- 3.9 ppb) and stable (5.0 +/- 2.5 ppb) patients. Sputum NO2/NO3 was significantly higher in acute patients (774 +/- 307 micromol/L) when compared with both stable patients (387 +/- 203 micromol/L) and control (421 +/- 261 micromol/L) subjects. Sputum NO2/NO3 did not return to normal in a subgroup of patients assessed after 2 wk of intensive antibiotic and glucocorticoid treatment. These results confirm that exhaled NO is not a useful measure of airway inflammation in CF. Elevated levels of sputum NO2/NO3 suggest that NOS is activated during acute pulmonary exacerbations of CF.
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