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.
Highlights
Abbreviations BC Breast cancer breast cancer cells (BCC) Breast cancer cell Tumor-infiltrating lymphocytes (TILs) Tumor infiltrating lymphocytes NK Natural killer NK-TILs Tumor infiltrating natural killer cell tumor microenvironment (TME) Tumor microenvironment IHC Immunohistochemistry overall survival (OS) Overall survival disease free survival (DFS) Disease free survival SBR Scarff–Bloom–Richardson TNM Tumor, lymph node and metastases LA Luminal A LB-Like Luminal B like H Her[2] positive
Representative examples of B7-H6 and PD-L1immunostaining in breast cancer cells (BCC) and TILs are shown in Fig. 1c,d respectively
In order to investigate the correlation between clinical parameters and the B7-H6 and PD-L1protein expression levels in BCC, we categorized the 156 patients into two major subgroups according to the intensity of B7-H6 and PD-L1immunohistochemical staining
Summary
Abbreviations BC Breast cancer BCC Breast cancer cell TILs Tumor infiltrating lymphocytes NK Natural killer NK-TILs Tumor infiltrating natural killer cell TME Tumor microenvironment IHC Immunohistochemistry OS Overall survival DFS Disease free survival SBR Scarff–Bloom–Richardson TNM Tumor, lymph node and metastases LA Luminal A LB-Like Luminal B like H Her[2] positive. Breast cancer is the most diagnosed malignancy in women worldwide and is a highly heterogeneous disease presenting a broad range of molecular and clinical c haracteristics[1] Towards this heterogeneity, the establishment of an effective immune response requires the participation of several actors. The most prominent immune checkpoint regulators are programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) and CTL antigen 4 (CTLA-4) These are highlighted in a variety of cancers and their therapeutic advances have encouraged researchers to investigate other targets from the B7/CD28 family. Five new B7 family ligands, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7, were identified and increasingly investigated in various solid cancers to seek significant association with cancer progression and patient prognosis in different clinical retrospective s tudies[9,10,11,12]. In the case of breast cancer disease, B7-H6 expression was revealed to be an unfavorable prognosis b iomarker[21]
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