Liyun Xu

Background: Malignant pleural effusion (MPE) correlates with poor prognosis. Tumor-associated macrophages dominate the immune microenvironment and govern MPE progression, while the functional heterogeneity of macrophage subsets in MPE remains poorly understood. CD169 ⁺ macrophages exhibit context-dependent tumor-regulatory functions in various malignancies, yet their phenotypic characteristics and biological roles in MPE remain uncharacterized. Methods: CD169⁺ macrophages and their CD169 ^low small and CD169 ^high large subsets were characterized in PPE, IPE, and lung adenocarcinoma-associated MPE, as well as in a murine MPE model, by flow cytometry. Their associations with MPE control were analyzed. The effects of CXCL2/CXCR2 signaling on macrophage migration, proliferation, and apoptosis were evaluated using recombinant human CXCL2 and the CXCR2 inhibitor SB225002 in vitro , and the therapeutic effects of CXCR2 inhibition were assessed in vivo . Results: CD169⁺ macrophages, including CD169 ^low small and CD169 ^high large macrophages, were significantly enriched in lung adenocarcinoma-associated MPE ( P < 0.05). Only CD169 ^high large macrophages were negatively associated with MPE control ( P < 0.05) and exhibited an immunosuppressive phenotype. Macrophages were the predominant CXCL2-expressing population in single-cell analysis. CXCL2 promoted macrophage migration, whereas CXCR2 inhibition with SB225002 attenuated this effect without affecting macrophage proliferation or apoptosis. In vivo , SB225002 reduced pleural effusion volume, CD169 ^high macrophage accumulation, and tumor burden. Conclusions: We identified a distinct population of CD169 ^high large macrophages that is enriched in lung adenocarcinoma-associated MPE and exhibits an immunosuppressive phenotype. CXCL2/CXCR2 axis promotes macrophage migration and contributes to the accumulation of CD169 ^high macrophages in the MPE microenvironment, thereby facilitating MPE progression. These findings provide new insights into the myeloid-cell regulatory mechanisms underlying MPE and may represent a potential therapeutic strategy for lung cancer-associated MPE.

Introduction: Tertiary lymphoid structures (TLSs) have been associated with the prognosis of various solid tumors. However, the association between TLSs and the prognosis of invasive lung adenocarcinoma (IAC) remains unclear in terms of location, density, and maturity. Methods: We retrospectively reviewed the clinicopathological characteristics of 750 patients with IAC. The density of TLSs in various tumor regions, as well as their maturation status, was examined by pathologists. The X-tile software was employed to determine the optimal cut-off values for the intratumoral and peritumoral TLS density based on overall survival. A threshold of 1.33 TLSs/cm ² was used to distinguish between low- and high-density intratumoral TLSs, while a threshold of 1.39 TLSs/cm ² was applied for peritumoral TLSs. Tissue slides exhibiting no or early TLSs demonstrated low maturation levels, while those with at least one lymphoid follicle indicated high maturation. We analyzed the correlation between TLS characteristics and clinicopathological parameters and assessed the impact of multiple clinicopathological factors on patient prognosis using Cox regression and Kaplan–Meier analyses. A multivariate logistic regression analysis model was used to explore predictive factors for the density of intratumoral TLSs and TLS maturity in patients with IAC. Results: Lower intratumoral TLS density, increased TLS maturation, lymph node metastasis, and the presence of solid (≥30%) and micropapillary (≥5%) pathological subtypes were identified as poor independent prognostic factors for overall survival in patients with IAC. Solid (≥30%) and micropapillary (≥5%) pathological subtypes were predictive factors for lower intratumoral TLS density (hazard ratio [HR] = 0.434, 95% confidence interval [CI] = 0.267-0.706, P = 0.001), while higher TLSs maturity was associated with a smoking history or pleural invasion (HR = 1.655, 95% CI = 1.048-2.613, P = 0.031; HR = 1.933, 95% CI = 1.054-3.546, P = 0.033). Conclusions: Both intratumoral TLS density and TLS maturation are independent prognostic factors for IAC. Additionally, higher TLS density predicted better prognosis, whereas greater TLS maturity predicted worse prognosis.

Monocytes, a crucial element of the innate immune system, act as the primary cells in the body’s immune response. Approved by the International Federation for Immunology in 2010, monocytes are categorized into three subsets based on the degree of cell surface molecule expression: classical monocytes, intermediate monocytes, and non-classical monocytes. Generally, different monocyte subsets have diverse responsibilities and can mutually transform to maintain the stability of the internal environment. Distinctions in functional characteristics and associations with diseases have been identified among the various monocyte subsets. This review aims to describe the expression and functions of monocytes in detail and discuss their roles in cancer immunity, which offers a novel approach for the diagnosis, treatment, and prognosis of tumors by exploring and summarizing the distribution of monocyte subsets in tumors. By delving into the distribution and functional characteristics of different monocyte subsets in tumors, it holds the promise of guiding individualized therapies and more precise tumor management.

Objectives: Interleukin‐6 (IL‐6) is critical for the development of non‐small‐cell lung cancer (NSCLC). Recently, we identified T‐cell immunoglobulin domain and mucin domain 4 (TIM‐4) as a new pro‐growth player in NSCLC progression. However, the role of TIM‐4 in IL‐6‐promoted NSCLC migration, invasion and epithelial‐to‐mesenchymal transition (EMT) remains unclear.Materials and Methods: Expressions of TIM‐4 and IL‐6 were both evaluated by immunohistochemical staining in NSCLC tissues. Real‐time quantitative PCR (qPCR), Western blot, flow cytometry and RT‐PCR were performed to detect TIM‐4 expression in NSCLC cells with IL‐6 stimulation. The roles of TIM‐4 in IL‐6 promoting migration and invasion of NSCLC were detected by transwell assay. EMT‐related markers were analysed by qPCR and Western blot in vitro, and metastasis was evaluated in BALB/c nude mice using lung cancer metastasis mouse model in vivo.Results: High IL‐6 expression was identified as an independent predictive factor for TIM‐4 expression in NSCLC tissues. NSCLC patients with TIM‐4 and IL‐6 double high expression showed the worst prognosis. IL‐6 promoted TIM‐4 expression in NSCLC cells depending on NF‐κB signal pathway. Both TIM‐4 and IL‐6 promoted migration, invasion and EMT of NSCLC cells. Interestingly, TIM‐4 knockdown reversed the role of IL‐6 in NSCLC and IL‐6 promoted metastasis of NSCLC by up‐regulating TIM‐4 via NF‐κB.Conclusions: TIM‐4 involves in IL‐6 promoted migration, invasion and EMT of NSCLC.

It is known that dysregulation of the immune system is closely related to the development of lung cancer and that CD8+T lymphocytes play a critical role in antitumor immunity. We analyzed the percentage of CD3+CD8+ T cells in peripheral blood, and expressions of the activated molecules, perforin, CD95, CD28, HLA-DR and CD38 in circulating CD3+CD8+ T cells from 68 lung cancer cases with stage I∼II and 61 lung cancer cases with stage III∼IV by flow cytometry. 61 lung cancer cases with stage III∼IV were followed up for more than 6 months and survival time was recorded. The percentages of perforin+ cells, CD95+ cells and CD38+ cells in fresh CD3+CD8+ T lymphocytes of stage III∼IV group were lower than those of stage I∼II group (p=0.021; p=0.043; p=0.036). And an increased percentage of CD3+CD8+perforin+ cells was shown to have a positive effect on the survival time in stage III∼IV lung cancer patients (p=0.043). Advanced lung cancer patients have characteristics of impairment in the cytotoxicity of circulating CD3+CD8+ T lymphocytes and perforin expression in circulating CD3+CD8+ T cells might be used as a prognostic biomarker for the advanced lung cancer.

Monocytes and associated cytokines have been shown to be involved in the pathogenesis of ankylosing spondylitis (AS). T cell immunoglobulin and mucin domain 4 (Tim-4) was identified on monocytes/macrophages and dentritic cells (DCs) and plays important roles in regulating the activities of macrophages and DCs. The current study investigated the association between Tim-4 expression and AS. Our results showed that Tim-4 expression on monocytes and Tim-4 level in plasma were highly increased in AS patients than in controls. Furthermore, TNF-α production and bath ankylosing spondylitis disease activity index (BASDAI) have positive relationships with Tim-4 expression in AS patients. High expression of Tim-4 was thought to contribute to the pathogenesis and an underlying mechanism of AS.