Divergent Cellular Expression Patterns of PD-L1 and PD-L2 Proteins in Breast Cancer

PD-L1 immunohistochemistry (IHC) has become an established method for predicting cancer response to targeted anti-PD1 immunotherapies, including breast cancer (BC). The alternative PD-1 ligand, PD-L2, remains understudied but may be a complementary predictive marker. Prospective analysis of 32 breast cancers revealed divergent expression patterns of PD-L1 and PD-L2. PD-L1-positivity was higher in immune cells than in cancer cells (median = 5.0% vs. 0.0%; p = 0.001), whereas PD-L2-positivity was higher in cancer cells than immune cells (median = 30% vs. 5.0%; p = 0.001). Percent positivity of PD-L1 and PD-L2 were not correlated, neither in cancer cells nor immune cells. Based on a cut-point of ≥1% positivity, ER+ tumors (n = 23) were frequently PD-L2-positive (73.9%), whereas only 40.9% were PD-L1-positive. These data suggest differential control of cellular PD-L1 and PD-L2 expression in BC and a potential role for PD-L2 IHC as a complementary marker to PD-L1 to improve selection of aggressive ER+ BC that may benefit from anti-PD-1 therapy.