Immune checkpoint molecules B7-H6 and PD-L1 co-pattern the tumor inflammatory microenvironment in human breast cancer

Abstract

B7-H6 and PD-L1 belong to the B7 family co-stimulatory molecules fine-tuning the immune response. The present work investigates the clinical effect of B7-H6 protein expression with PD-L1 status and the infiltration of natural killer cells as potential biomarkers in breast tumor inflammatory microenvironment. The expression levels of B7-H6 protein by cancer cells and immune infiltrating cells in human breast cancer tissues and evaluate their associations with PD-L1 expression, NK cell status, clinical pathological features and prognosis were explored. The immunohistochemistry labeling method was used to assess B7-H6 and PD-L1 proteins expression by cancer and immune cells. The associations between immune checkpoint, major clinical pathological variables and survival rates were analyzed. B7-H6 protein was depicted in both breast and immune cells. Results showed that Tumor B7-H6 expression is highly associated with Her-2 over expression. B7-H6 + immune cells are highly related to the Scarff–Bloom–Richardson grade and associated with PD-L1 expression and NK cells status. Survival analysis revealed a better prognosis in patients with low expression of B7-H6 by cancer cells. Conversely, B7-H6 + immune cells were significantly associated with longer survival. Findings strongly suggest an interaction between B7 molecules that contributes to a particular design of the inflammatory microenvironment. This may influence the efficiency of therapies based on antibodies blocking the PD-L1/PD1 pathway and can explain the detection of clinical benefits only in a fraction of patients treated with immune checkpoint inhibitors.

Clinical significance and correlation of PD-L1, B7-H3, B7-H4, and TILs in pancreatic cancer

“…Growing numbers of research have reported that mutually-exclusive or co-expressed patterns of B7 molecules could predict inflamed or non-inflamed TME in multiple human cancers [14,29]. For example, B7-H4 is negatively correlated with PD-L1 and identifies immuno-cold tumors in glioma [14].…”

Co-deficiency of B7-H3 and B7-H4 identifies high CD8 + T cell infiltration and better prognosis in pancreatic cancer

“…Given co-expressed or mutually-exclusive patterns of B7 molecules predict inflamed or non-inflamed TME in multiple human cancers [ 14 , 15 ], we next assess whether co-deficiency of B7-H3 and B7-H4 predicted specific TME features. The xCell tool was used to estimate the abundance of 64 immune and stromal cell types in the TCGA database, and the abundance of these cells in the co-low, single-high and co-high groups were next compared.…”

“…According to previous reports, B7-H3 and B7-H4 are significantly up-regulated in PAAD tissues compared with non-tumor or normal pancreas tissues [ 12 , 13 ]. Besides, co-expressed or mutually-exclusive patterns of B7 molecules predict inflamed or non-inflamed TME in multiple human cancers [ 14 , 15 ]. However, the correlation between B7-H3 and B7-H4 expression and TIICs abundance as well as the predictive value of combined B7-H3 and B7-H4 in assessing prognosis has not been investigated yet.…”

Programmed cell death-1 and its ligands: Current knowledge and possibilities in immunotherapy

“…The role of B7-H6 in the inflammatory tumor microenvironment design was sought via the relationship of its expression with PD-L1 and NK-TILs status. 27 The impressive results obtained with immunotherapy in other chemoresistant tumors such as melanoma and renal cancer have raised interest in the potential for using this approach in patients with gynecologic cancers. This has led to the development of a large number of clinical trials testing immunotherapy both as monotherapy and in combination with other strategies such as chemotherapy, targeted agents, or both.…”