Tumor-associated macrophage, angiogenesis and lymphangiogenesis markers predict prognosis of non-small cell lung cancer patients

作者：Ilseon Hwang, Jeong Won Kim, Kris Ylaya, Eun Joo Chung, Haruhisa Kitano, Candice Perry, Jun Hanaoka, Junya Fukuoka, Joon‐Yong Chung, Stephen M. Hewitt · 发表于：Journal of Translational Medicine · 年份：2020 · DOI：10.1186/s12967-020-02618-z · 被引用次数：266 · 研究领域：Immune cells in cancer、Lymphatic System and Diseases、Angiogenesis and VEGF in Cancer

Abstract Background The 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). Methods Utilizing 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. Results CD68 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 ratio high and VEGF-C high (M2 ratio high VEGF-C high ) was correlated with worse overall survival ( p = 0.033). Multivariate analysis revealed that M2 ratio high [HR (95% CI) = 1.53 (1.01–2.33), p = 0.046] and combined M2 ratio high VEGF-C high expression [HR (95% CI) = 2.01 (1.28–3.16), p = 0.003] were independent...