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

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 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. Conclusions This 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.

Combination of Immunotherapy and Radiotherapy for Recurrent Malignant Gliomas: Results From a Prospective Study

“…CD68 is a major biomarker for the quantification of tumor-associated macrophages (TAMs) (48). As we all know, TAMs are a wellrecognized core element of tumor microenvironment (TME) and generally characterized as M2-like macrophages which are associated with tumor progression and poor prognosis (49,50). This is the reason that high tumor CD15 and CD68 expression indicates a limited response and poor survival.…”

Prognostic Significance of Tumor-Associated Macrophages in Chondroblastoma and Their Association with Response to Adjuvant Radiotherapy

“…A negative control was produced by replacing the primary antibody with a phosphate buffer solution, and a positive control was generated using human testis tissues according to a previous report. 14 …”

“…11,12 Furthermore, for patients with colon cancer and non-small cell lung cancer, the inclusion of the CD163+/CD68+ ratio was found to significantly improve the accuracy of traditional tumor-node metastasis staging in predicting patient outcomes. 13,14 Previous studies have demonstrated that many factors can affect CB prognosis. For example, it has been reported that CB lesions located in the pelvis and proximal humerus have a poor prognosis.…”

“… 11 , 12 Furthermore, for patients with colon cancer and non-small cell lung cancer, the inclusion of the CD163+/CD68+ ratio was found to significantly improve the accuracy of traditional tumor-node metastasis staging in predicting patient outcomes. 13 , 14 …”

MERTK Inhibition: Potential as a Treatment Strategy in EGFR Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer

“…Most of the tumor-associated macrophages resemble M2-like macrophages. Unlike M1-like macrophages with pro-inflammatory and anti-cancer activities, the M2-like macrophages function as immunosuppressive cells contributing to tumor initiation, angiogenesis, drug resistance, and metastasis [ 147 , 148 ]. The M2 macrophages help the immunosuppressive microenvironment by releasing anti-inflammatory cytokines, such as IL-20, TGF-β, and HGF [ 149 ], or by preventing the release of intracellular antigens from apoptotic cancer cells via efferocytosis [ 150 ].…”