Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with advanced non-small-cell lung cancer treated with nivolumab.

BACKGROUND: There is an unmet need to identify markers that predict the response to nivolumab in patients with non-small-cell lung cancer (NSCLC). The neutrophil-to-lymphocyte ratio (NLR) was recently recognized as an indicator of a poor prognosis in patients with various cancers. In the present study, we quantified the predictive impact of NLR in patients with NSCLC treated with nivolumab. METHODS: We retrospectively analyzed 101 patients with advanced NSCLC treated with nivolumab at Kansai Medical University Hospital from December 2015 to December 2016. Patients were administered nivolumab at a dose of 3 mg/kg every 2 weeks. The predictive value of NLR for disease progression before treatment and 2 and 4 weeks after nivolumab treatment was assessed. RESULTS: The median progression-free survival (PFS) of patients with an NLR of < 3 before treatment was 3.4 months, whereas that of patients with an NLR of ≥ 3 was 2.9 months (p = 0.484). The median PFS of patients with an NLR of < 3 at 2 weeks after treatment was 5.3 months, whereas that of patients with an NLR of ≥ 3 was 2.1 months (p = 0.00528). The median PFS of patients with an NLR of < 3 at 4 weeks after treatment was 5.3 months, whereas that of patients with an NLR of ≥ 3 was 2.0 months (p = 0.00515). CONCLUSION: The NLR at 2 and 4 weeks after treatment might be a useful marker for the prediction of the treatment response or disease progression in patients with advanced NSCLC receiving nivolumab.

Retrospective analysis of single-agent nab-paclitaxel in patients with platinum-resistant non-small cell lung cancer.

A retrospective study was conducted to investigate the efficacy and toxicity of single-agent nab-paclitaxel in 67 patients with platinum-resistant non-small cell lung cancer in Kansai Medical University Hospital from August 2013 to December 2015. Overall, 25% of patients experienced disease progression, 48% exhibited a partial response, 27% had stable disease and 0% had a complete response. The median progression-free survival (PFS) time was 4.8 months and the median overall survival time was 18.2 months. There was no statistically significant difference in PFS between patients with non-squamous carcinoma and squamous carcinoma, or between second-line use and post-second-line use. The most common severe adverse event was neutropenia, followed by interstitial lung disease, infection and fatigue. The results revealed that single agent nab-paclitaxel was associated with an acceptable level of toxicity and a favorable response. This regimen has been developed recently, thus it has not been sufficiently evaluated its toxicity and efficacy. Additional studies to evaluate these parameters in non-small cell lung cancer are warranted.

Interstitial Lung Disease Following Single-Agent Nanoparticle Albumin-Bound Paclitaxel Treatment in Patients with Advanced Non-Small Cell Lung Cancer.

Interstitial lung disease (ILD) is a serious and potentially fatal adverse event in lung cancer therapy. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a novel, solvent-free formulation of paclitaxel (PTX). Although the incidence of nab-PTX-induced ILD is not clear, it is generally considered that this formulation presents a similar risk of developing ILD as PTX. Here, we report 3 patients who developed severe ILD following treatment with nab-PTX. We draw attention to the risk of developing drug-induced ILD following nab-PTX treatment, and highlight that this novel formulation might therefore not be as safe as PTX with respect to the development of ILD.

IL-33 promotes the induction and maintenance of Th2 immune responses by enhancing the function of OX40 ligand.

BACKGROUND: In Th2 immune responses, TSLP is a key player by induction of OX40-ligand (OX40L) on dendritic cells (DCs), which is the trigger to induce Th2 cell-mediated allergic cascade. Thus, TSLP-DC-OX40L axis might be the principal pathway in the inflammatory cascades in atopic dermatitis and asthma. IL-33, which is produced by epithelial cells, has been implicated in the Th2 immune responses and pathogenesis of the allergic disorders. However, the role of IL-33 in the Th2-polarizing TSLP-DC-OX40L axis still remains largely elusive. We focused on the ability of IL-33 to promote OX40L-mediated Th2 responses. METHODS: Purified human naïve or memory CD4+ T cells were stimulated with recombinant OX40L or TSLP-treated DCs (TSLP-DCs) in the presence of IL-33, and the cytokine production by the primed T cells was examined. We also performed immunohistochemical analyses for the expression of IL-33 in specimens of lymph node and skin from the patients with atopic dermatitis. RESULTS: IL-33 remarkably enhanced TSLP-DCs-driven or OX40L-driven Th2 responses from naïve T cells and the Th2 functional attributes of CRTH2+ CD4+ Th2 memory cells by the increased production of IL-5, IL-9, and IL-13. In addition, IL-33 was expressed in the nuclei of epithelial cells in not only skin lesion but also lymph nodes of the patient with atopic dermatitis, suggesting a specialized role in adaptive T cell-priming phase. CONCLUSIONS: IL-33 works as a positive regulator of TSLP-DC-OX40L axis that initiates and maintains the Th2 cell-mediated inflammatory responses, and therefore, it would be a new therapeutic target for the treatment of allergic disorders.

IL-33 Promotes the Induction and Maintenance of Th2 Immune Responses by Enhancing the Function of OX40 Ligand.

BACKGROUND: In Th2 immune responses, TSLP is a key player by induction of OX40-ligand (OX40L) on dendritic cells (DCs), which is the trigger to induce Th2 cell-mediated allergic cascade. Thus, TSLP-DC-OX40L axis might be the principal pathway in the inflammatory cascades in atopic dermatitis and asthma. IL-33, which is produced by epithelial cells, has been implicated in the Th2 immune responses and pathogenesis of the allergic disorders. However, the role of IL-33 in the Th2-polarizing TSLP-DC-OX40L axis still remains largely elusive. We focused on the ability of IL-33 to promote OX40L-mediated Th2 responses. METHODS: Purified human naïve or memory CD4+ T cells were stimulated with recombinant OX40L or TSLP- treated DCs (TSLP-DCs) in the presence of IL-33, and the cytokine production by the primed T cells was examined. We also performed immunohistochemical analyses for the expression of IL-33 in specimens of lymph node and skin from the patients with atopic dermatitis. RESULTS: IL-33 remarkably enhanced TSLP-DCs-driven or OX40L-driven Th2 responses from naïve T cells and the Th2 functional attributes of CRTH2+ CD4+ Th2 memory cells by the increased production of IL-5, IL-9, and IL-13. In addition, IL-33 was expressed in the nuclei of epithelial cells in not only skin lesion but also lymph nodes of the patient with atopic dermatitis, suggesting a specialized role in adaptive T cell-priming phase. CONCLUSIONS: IL-33 works as a positive regulator of TSLP-DC-OX40L axis that initiates and maintains the Th2 cell-mediated inflammatory responses, and therefore, it would be a new therapeutic target for the treatment of allergic disorders.

Plasmacytoid dendritic cells have a cytokine-producing capacity to enhance ICOS ligand-mediated IL-10 production during T-cell priming.

Plasmacytoid dendritic cells (pDCs) have the potential to prime CD4(+) T-cells to differentiate into IL-10-producing T regulatory cells through preferential expression of inducible co-stimulatory ligand (ICOS-L). Although pDCs produce cytokines such as type-I IFNs, TNF-α, or IL-6 accompanying up-regulation of ICOS-L expression during activation in response to toll-like receptor (TLR)-ligands or IL-3, the roles of the pDC-derived cytokines in T-cell priming remain largely elusive. Therefore, we investigated the functional involvement of these cytokines in generating IL-10-producing T regulatory cells. We found that either IFN-α or IL-6 enhanced the pDC- or ICOS-L-driven generation of IL-10-producing T-cells from naive CD4(+) T-cells and their regulatory functions. However, IFN-α stimulation in the absence of ICOS-L showed only a marginal tendency to increase the T-cell production of IL-10 and thus pDC-derived type-I IFNs in response to CpG could function together with ICOS-L. In addition, IL-6 functioned to generate IL-10-producing T-cells only on T-cell priming by pDCs activated by IL-3 or under IL-4-mediated T(h)2 conditions. Thus, type-I IFNs and IL-6 act as supplementary factors for the ICOS-L-dependent IL-10-producing T-cell differentiation in pDCs activated along the TLR-dependent and IL-3-dependent pathways, respectively. We also showed that pDC-derived TNF-α induced ICOS-L expression on pDCs in an autocrine manner and that IL-6 promoted ICOS expression on T-cells, contributing to the ICOS/ICOS-L-mediated T-cell response. Our results suggest that the ICOS-L-mediated tolerogenic pDC function in adaptive immunity is backed up by the elaborate cytokine-producing ability of pDCs.