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.
Given the close interaction between tumor cells and stromal cells in the tumor microenvironment (TME), TME-targeted strategies would be promising for developing integrated cancer immunotherapy. Cancer-associated fibroblasts (CAFs) are the dominant stromal component, playing critical roles in generation of the pro-tumorigenic TME. We focused on the immunosuppressive trait of CAFs, and systematically explored the alteration of tumor-associated immune responses by CAF-targeted therapy. C57BL/6 mice s.c. bearing syngeneic E.G7 lymphoma, LLC1 Lewis lung cancer, or B16F1 melanoma were treated with an anti-fibrotic agent, tranilast, to inhibit CAF function. The infiltration of immune suppressor cell types, including regulatory T cells and myeloid-derived suppressor cells, in the TME was effectively decreased through reduction of stromal cell-derived factor-1, prostaglandin E2, and transforming growth factor-β. In tumor-draining lymph nodes, these immune suppressor cell types were significantly decreased, leading to activation of tumor-associated antigen-specific CD8+ T cells. In addition, CAF-targeted therapy synergistically enhanced multiple types of systemic antitumor immune responses such as the cytotoxic CD8+ T cell response, natural killer activity, and antitumor humoral immunity in combination with dendritic cell-based vaccines; however, the suppressive effect on tumor growth was not observed in tumor-bearing SCID mice. These data indicate that systemic antitumor immune responses by various immunologic cell types are required to bring out the efficacy of CAF-targeted therapy, and these effects are enhanced when combined with effector-stimulatory immunotherapy such as dendritic cell-based vaccines. Our mouse model provides a novel rationale with TME-targeted strategy for the development of cell-based cancer immunotherapy.
EOB-MRI represents a practical and reliable imaging technique that may be used to estimate regional liver functional reserve in the clinical setting.
IntroductionThe contribution of programmed cell death ligand-1 (PD-L1) immune checkpoint molecule toward progression of non-small cell lung cancer (NSCLC) has not yet been elucidated, in part, because of lack of a standardised method to evaluate PD-L1 expression. In this study, we developed a novel method for the evaluation of PD-L1 expression on NSCLC cells and examined its correlation with clinicopathological characteristics.MethodsAfter immunohistochemical examination of PD-L1 expression for surgically resected pulmonary adenocarcinomas (n=106), based on the findings that PD-L1 are consistently expressed on alveolar macrophages, PD-L1 staining intensity of tumour cells was classified into four levels relative to PD-L1 staining intensity in alveolar macrophages; PD-L1 expression scores (range, 0–300) were semiquantitatively assessed. An analysis of statistical association between PD-L1 expression score and clinicopathological characteristics was performed.ResultsAlmost all of the alveolar macrophages in the specimens were moderately to strongly stained with PD-L1, serving as an internal positive control in the immunohistochemistry of PD-L1. PD-L1 expression score (median, 52.3) was significantly higher in tumours with G2/3 differentiation than in those with G1 (p=0.022) and higher in those with lymphatic invasion than in those without invasion (p=0.032). Postoperative relapse-free survival was significantly shorter in patients with a high PD-L1 expression score than in those with low PD-L1 expression score (p=0.035). Smoking habits, histological subtype, and epidermal growth factor receptor mutation status were not associated with PD-L1 expression score.ConclusionsGiven the heterogeneous distribution of PD-L1 expression in pulmonary adenocarcinoma cells, the scoring of PD-L1 expression on tumour cells relative to that in alveolar macrophages appears to be a valid indicator of PD-L1 status of patients with pulmonary adenocarcinomas, demonstrating a significant correlation with several factors associated with tumour progression.
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