Prognostic significance of programmed death ligand 2 expression in tumor-infiltrating lymphocytes of triple-negative breast cancer

Objectives: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and overexpression of human epidermal growth factor receptor 2 protein. Patients with high expression of programmed death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) have been found to have better prognosis and increased response to anti-PD-1/PDL1 immunotherapy. However, the role programmed death ligand 2 (PD-L2), the other known ligand of PD-1, plays in PD-1/PD-L1 checkpoint pathway has not been well studied. Therefore, this project aims to investigate (1) the relationship between PD-L2 expression in tumor infiltrating lymphocytes (TILs) and patient clinicopathological features, (2) whether PD-L2 can serve as a predictor of patient survival, and (3) the association of PD-L2 expression with the infiltration of relevant immune cell types in the tumor microenvironment. Materials and Methods: Two hundred and ninety-six (296) TNBC cases diagnosed between 2003 and 2013 in Singapore General Hospital were used in this study to create tissue microarray for immunohistochemistry with several antibodies. Results: Patients with PD-L2 expression were found to have significantly improved disease-free survival (hazard ratio [HR] 0.51; P = 0.0362) and overall survival (HR 0.43; P = 0.0379) compared to patients who have negative PD-L2 expression. PD-L2 + TILs correlate significantly with CD3 + T-cells ( P = 0.00776) and CD20 + B-cells ( P = 0.001019) infiltration in the stromal compartments and intratumoral CD38 + plasma cells ( P = 0.048869) infiltration. Conclusion: Like PD-L1, PD-L2 positivity in TILs was found in our study to indicate a better prognosis compared to PD-L2-negative patients.