Abstract
BackgroundThe tumor microenvironment (TME) is a critical player in tumor progression, metastasis and therapy outcomes. Tumor-associated macrophages (TAMs) are a well-recognized core element of the TME and generally characterized as M2-like macrophages. TAMs are believed to contribute to tumor progression, but the mechanism behind this remains unclear. We aimed to investigate the clinical, angiogenic, and lymphangiogenic significance of TAMs in non-small cell lung cancer (NSCLC).MethodsUtilizing combined immunohistochemistry and digital image analysis, we assessed CD68, CD163, VEGF-A, and VEGF-C expression in 349 patients with NSCLC. Subsequently, the potential association between M2 TAMs and angiogenic VEGF-A and/or lymphangiogenic VEGF-C was evaluated for its prognostic value. Furthermore, the effects of M2 TAMs on angiogenesis and lymphangiogenesis were explored via an in vitro co-culture system.ResultsCD68 and CD163 expression were found to directly correlate with VEGF-A and/or VEGF-C expression (all p < 0.001). Furthermore, elevated M2 ratio (CD163+/CD68+) was significantly associated with poor overall survival (p = 0.023). Dual expression of M2 ratiohigh and VEGF-Chigh (M2 ratiohighVEGF-Chigh) was correlated with worse overall survival (p = 0.033). Multivariate analysis revealed that M2 ratiohigh [HR (95% CI) = 1.53 (1.01–2.33), p = 0.046] and combined M2 ratiohighVEGF-Chigh expression [HR (95% CI) = 2.01 (1.28–3.16), p = 0.003] were independent predictors of poor overall survival. Notably, we confirmed that M2 macrophages significantly enhanced the protein and mRNA expression of both VEGF-A and VEGF-C, while M1 macrophages induced only mRNA expression of VEGF-A in A549 cells.ConclusionsThis study suggests that TAMs are significantly associated with angiogenesis and lymphangiogenesis, contributing to the progression of NSCLC. Furthermore, elevated M2 ratio, similar to combined high M2 ratio and high VEGF-C expression, is a strong indicator of poor prognosis in patients with NSCLC, providing insight for future TAM-based immunotherapy strategies.
Highlights
The tumor microenvironment (TME) is a critical player in tumor progression, metastasis and therapy outcomes
Programmed death ligand 1 (PDL1) expression on tumor cells [4, 5], tumor mutation burden (TMB) [6, 7], tumor-infiltrating lymphocytes (TILs) [8], microsatellite instability (MSI) [9], tumor microenvironment (TME) [10], and microbiome [11] are factors taken under consideration when administering immune checkpoints inhibitors to non-small cell lung cancer (NSCLC) patients
Survival analysis of Tumor associated macrophage (TAM), vascular endothelial growth factor (VEGF)‐A, and VEGF‐C expression We examined the relationship between TAMs, VEGF-A, and VEGF-C expression and patient survival outcomes in 349 NSCLC patients with available overall survival data
Summary
The tumor microenvironment (TME) is a critical player in tumor progression, metastasis and therapy outcomes. Lung cancer is the primary cause of cancer-related deaths worldwide, and is characterized by a poor prognosis in its advanced stages [1]. The tumor, node, metastasis (TNM) staging system approved by the International Association for the Study of Lung Cancer (IASLC) and the American Joint Committee on Cancer (AJCC) is used internationally to characterize the extent of disease and its correlations with survival. Programmed death ligand 1 (PDL1) expression on tumor cells [4, 5], tumor mutation burden (TMB) [6, 7], tumor-infiltrating lymphocytes (TILs) [8], microsatellite instability (MSI) [9], tumor microenvironment (TME) [10], and microbiome [11] are factors taken under consideration when administering immune checkpoints inhibitors to NSCLC patients. More effective biomarkers are necessary to better predict the effectiveness of immunotherapy and improve risk stratification before treatment
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