B7-H3 in combination with regulatory T cell is associated with tumor progression in primary human non-small cell lung cancer

Abstract

B7-H3 belongs to the co-inhibitory B7 family and plays an important role in the adaptive immune response in regulating T cells. In human malignancies, B7-H3 is reported to be involved in tumor immune evasion. However, the detailed molecular mechanism of B7-H3 in tumor evasion remains unclear, particularly in non-small cell lung cancer (NSCLC). Regulatory T cells (Tregs) are known as a key player in the inhibition of immune mechanisms. The study demonstrated the correlation between B7-H3 on tumor cells and the number of Tregs in the tumor microenvironment in NSCLC. B7-H3 was examined in tumor tissues from 110 patients with NSCLC by immunohistochemical analysis. Forkhead box P3+ (FOXP3+) Tregs in those spencimens were also detected and numbered. Survival curves were drawn using the Kaplan-Meier method and compared by the log-rank test. High B7-H3 expression in tumor cells significantly correlated with male gender, squamous NSCLC, advanced stage and shorter overall survival (OS) (P = 0.035, P = 0.004, P = 0.037, P = 0.014, respectively). Meanwhile, FOXP3 expression in tumor-infiltrating lymphocytes (TILs) was associated with male gender, regional lymph node involvement, advanced stage and worse OS (P = 0.009, P = 0.015, P = 0.014, P = 0.034, respectively). Significant correlation was identified between the expression of B7-H3 and the number of FOXP3+ TILs (P = 0.013). Patients with B7-H3 high/FOXP3 high had poorer OS (P = 0.006), suggesting that B7-H3 and Tregs may play a cooperatively role in tumor immune evasion, leading to poor outcomes for NSCLC patients.

Keywords: B7-H3; non-small cell lung cancer; regulatory T cell; tumor immune evasion.

Figure 1

Immunohistochemical analysis of B7-H3 expression in sections from primary NSCLC. B7-H3 expression is shown in both cell membrane and cytoplasm (brown staining). A: Negative expression of B7-H3 (200× magnification); B: Weak expression of B7-H3 (200× magnification); C: Moderate expression of B7-H3 (200× magnification); D: High expression of B7-H3 (200× magnification); E: Negative expression of B7-H3 (400× magnification); F: Weak expression of B7-H3 (400× magnification); G: Moderate expression of B7-H3 (400× magnification); H: High expression of B7-H3 (400× magnification).

Figure 2

Correlation of OS with B7-H3 expression in NSCLC cells. B7-H3 high was associated with significantly reduced OS in patients with NSCLC.

Figure 3

Immunohistochemical detection of FOXP3+ cell in sections from primary NSCLC. The ratio of FOXP3+ cell/TILs was categorized. A: Little expression of FOXP3+ cell (200× magnification); B: Low expression of FOXP3+ cell (200× magnification); C: Moderate expression of FOXP3+ cell (200× magnification); D: High expression of FOXP3+ cell (200× magnification); E: Little expression of FOXP3+ cell (400× magnification); F: Low expression of FOXP3+ cell (400× magnification); G: Moderate expression of FOXP3+ cell (400× magnification); H: High expression of FOXP3+ cell (400× magnification).

Figure 4

Correlation of OS with FOXP3+ cell in TILs of NSCLC tissues. FOXP3+ high was associated with significantly reduced OS in patients with NSCLC.

Figure 5

Correlation of B7-H3 expression in NSCLC cancer cells and FOXP3+ cell in TILs. The ratio of FOXP3+ in TILs was higher in B7-H3 high expression group in NSCLC.

Figure 6

Correlation of OS with B7-H3 high/FOXP3 high expression in NSCLC tissues. Patients with B7-H3 high/FOXP3 high relapsed within a shorter period than patients with B7-H3 low/FOXP3 low.