Background: The interaction of the PD-1 receptor on tumor infiltrating lymphocytes and PD-L1 on tumor cells dampens antitumor immunity. Two phase I trials suggested efficacy of anti-PD-1/PD-L1 antibodies in triple negative (TN) BC. This study investigated associations between primary BC PD-1 and PD-L1 expression, clinical characteristics, and patient outcomes in publically available databases. 

Methods: We evaluated PD-1 and PD-L1 expression using microarray data from the neoadjuvant I-SPY 1 study (n = 149). Associations with clinical features and chemotherapy response were assessed by Kruskal-Wallis and Wilcoxon rank sum tests, respectively. Recurrence free survival (RFS) associations were assessed by the Cox proportional hazard model. Pearson correlations between PD-1 and expression of PD-L1, HAVCR2, STAT5A, FOXP3, MYC, and ESR1 were determined in I-SPY 1 and 2 other datasets: METABRIC (n = 1992) and TCGA (n = 817).

 Results: In I-SPY 1, PD-1 expression was significantly higher in HER2+ and TNBC (p = 0.003), and in grade 2/3 tumors (p = 0.043); this association was also seen in METABRIC. PD-1 expression was associated with pathologic complete response (p = 0.006) but not with tumor stage, nodal status, lymphovascular invasion or RFS. While PD-L1 did not correlate with tumor features, patients with PD-L1 expression in the lowest quintile had worse RFS, even after subtype adjustment (HR 2.33, p = 0.01). In all 3 datasets, PD-1 significantly correlated with PD-L1, HAVCR2, and STAT5A, and inversely with ESR1. In the TN subset of TCGA and METABRIC, PD-1 significantly correlated with PD-L1, HAVCR2, and STAT5A. In TCGA and METABRIC, PD-L1 significantly correlated with HAVCR2 and STAT5A, and this was also seen in the TN subset. In TCGA alone, PD-1 and PD-L1 significantly correlated with FOXP3, and PD-1 with MYC. 

Conclusions: PD-1 expression is higher in TN and other aggressive BC subtypes. PD-1 and PD-L1 correlate with immune related genes HAVCR2 and STAT5A. Low PD-L1 expression may be an adverse prognostic factor. Trials are underway to investigate the activity of anti-PD-1/PD-L1 antibodies in TNBC and to elucidate markers of response.