Background:Lung cancer remains a major global health threat due to its complex microenvironment, particularly the role of neutrophils, which are crucial for tumor development and immune evasion mechanisms. This study aimed to delve into the impact of lung cancer cell-conditioned media on neutrophil functions and their potential implications for lung cancer progression.Methods:Employing in vitro experimental models, this study has analyzed the effects of lung cancer cell-conditioned media on neutrophil IL-8 and IFN-γ secretion, apoptosis, PD-L1 expression, and T-cell proliferation by using techniques, such as ELISA, flow cytometry, immunofluorescence, and CFSE proliferation assay. The roles of IL-8/PD-L1 in regulating neutrophil functions were further explored using inhibitors for IL-8 and PD-L1.Results:Lung cancer cell lines were found to secrete higher levels of IL-8 compared to normal lung epithelial cells. The conditioned media from lung cancer cells significantly reduced apoptosis in neutrophils, increased PD-L1 expression, and suppressed T-cell proliferation and IFN-γ secretion. These effects were partially reversed in the presence of IL-8 inhibitors in Tumor Tissue Culture Supernatants (TTCS), while being further enhanced by IL-8. Both apoptosis and PD-L1 expression in neutrophils demonstrated dose-dependency to TTCS. Additionally, CFSE proliferation assay results further confirmed the inhibitory effect of lung cancer cell-conditioned media on T-cell proliferation.Conclusion:This study has revealed lung cancer cell-conditioned media to modulate neutrophil functions through regulating factors, such as IL-8, thereby affecting immune regulation and tumor progression in the lung cancer microenvironment.

09 Aug 2024·ACS Pharmacology & Translational Science

A First Insight into the Developability of an Immunoglobulin G3: A Combined Computational and Experimental Approach

Article

Author: Jamieson, Craig J. ; Armstrong, Georgina B. ; Rattray, Zahra ; Burley, Glenn A. ; Lewis, William ; Taylor, Paul ; Shah, Vidhi ; Lewis, Alan

Immunoglobulin G 3 (IgG3) monoclonal antibodies (mAbs) are high-value scaffolds for developing novel therapies. Despite their wide-ranging therapeutic potential, IgG3 physicochemical properties and developability characteristics remain largely under-characterized. Protein-protein interactions elevate solution viscosity in high-concentration formulations, impacting physicochemical stability, manufacturability, and the injectability of mAbs. Therefore, in this manuscript, the key molecular descriptors and biophysical properties of a model anti-IL-8 IgG1 and its IgG3 ortholog are characterized. A computational and experimental framework was applied to measure molecular descriptors impacting their downstream developability. Findings from this approach underpin a detailed understanding of the molecular characteristics of IgG3 mAbs as potential therapeutic entities. This work is the first report examining the manufacturability of IgG3 for high-concentration mAb formulations. While poorer conformational and colloidal stability and elevated solution viscosity were observed for IgG3, future efforts controlling surface potential through sequence-engineering of solvent-accessible patches can be used to improve biophysical parameters that dictate mAb developability.

01 Aug 2024·Redox Biology

Lactate-induced activation of tumor-associated fibroblasts and IL-8-mediated macrophage recruitment promote lung cancer progression

Article

Author: Ding, Xu ; Su, Jincheng ; Jiang, Lei ; Zhu, Yifei ; Gu, Xuyu ; Su, Xiangyu ; Wang, Sheng ; Fei, Xiang ; Zhang, Wentian

Alterations in the tumor microenvironment are closely associated with the metabolic phenotype of tumor cells. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor growth and metastasis. Existing studies have suggested that lactate produced by tumor cells can activate CAFs, yet the precise underlying mechanisms remain largely unexplored. In this study, we initially identified that lactate derived from lung cancer cells can promote nuclear translocation of NUSAP1, subsequently leading to the recruitment of the transcriptional complex JUNB-FRA1-FRA2 near the DESMIN promoter and facilitating DESMIN transcriptional activation, thereby promoting CAFs' activation. Moreover, DESMIN-positive CAFs, in turn, secrete IL-8, which recruits TAMs or promotes M2 polarization of macrophages, further contributing to the alterations in the tumor microenvironment and facilitating lung cancer progression. Furthermore, we observed that the use of IL-8 receptor antagonists, SB225002, or Navarixin, significantly reduced TAM infiltration and enhanced the therapeutic efficacy of anti-PD-1 or anti-PD-L1 treatment. This finding indicates that inhibiting IL-8R activity can attenuate the impact of CAFs on the tumor microenvironment, thus restraining the progression of lung cancer.

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