Immune Checkpoint Molecules B7-H6 and PD-L1 Co-Pattern The Tumor Inflammatory Microenvironment: Associations and Clinical Significance in Human Breast Cancer

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Abstract B7-H6 and PD-L1 belong to the B7 family co-stimulatory molecules fine-tuning the immune response. This report exposes for the first time the clinical implication of B7-H6 protein expression in relation with PD-L1 status and Natural Killer Cells infiltration as potential biomarkers in tumor inflammatory microenvironment. Herein, we explore 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 and clinical pathological features as well as the prognosis. Immunohistochemistry labeling method was used to assess B7-H6 and PD-L1 proteins expression by cancer and immune cells. Associations between immune checkpoint, major clinicopathological variables and survival rates were analyzed. B7-H6 protein was revealed in both breast and immune cells. Tumor B7-H6 expression is highly associated with Her2 over expression. B7-H6 + immune cells are highly related to SBR grade and associated with PD-L1 and NK cells status. Survival analysis showed that patients with low expression of B7-H6 by cancer cells had better prognosis. Conversely, B7-H6 + immune cells were significantly associated with longer survival. Our result strongly suggests 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 why the clinical benefits are seen only in a fraction of patients treated with immune checkpoint inhibitors.

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