We recently reported that high cancer cell protein levels of PD-L2 in patients (pts) with treatment-naïve estrogen receptor-positive breast cancer (ER+ BC), was an independent predictor of shorter progression-free survival in two distinct cohort of pts (1). These findings suggest that PD-L2 may help improve BC pt selection for PD-1 inhibitors. We therefore initiated efforts to determine baseline expression patterns of PD-L1 and PD-L2 in BC.
PD-L1 and PD-L2 protein levels in cancer cells and tumor-infiltrating immune cells were prospectively analyzed by immunohistochemistry (IHC) using validated antibodies in diagnostic core biopsies of 28 consecutive pts diagnosed with localized or locoregional ER+/HER2- BC or TNBC. Percent positivity of PD-L1 and PD-L2 in cancer cells and immune cells was determined by a breast pathologist.
PD-L1 and PD-L2 expression patterns in BC differed in several ways. First, PD-L1-positivity in immune cells was higher than in cancer cells (median=5.0% vs. 0.05%; p=0.002), whereas PD-L2-positivity was higher in cancer vs. immune cells (median=20% vs. 5.0%; p=0.001). Second, there was no significant correlation between PD-L1 and PD-L2 expression, neither across all cases (N=28), nor within ER+ (N=20) or TNBC (N=8) cases. Third, PD-L1 positivity in cancer cells and immune cells were positively correlated in TNBC (
PD-L1 and PD-L2 proteins show divergent expression and are not correlated in BC. Discordant PD-L2 and PD-L1 expression may be more common in ER+ BC than in TNBC. This progress justifies efforts to explore PD-L2 as a complementary marker to PD-L1 for improved prediction of responses to PD-1 inhibitors, which may also benefit pts with aggressive ER+ BC. Reference: 1.JCO Precis Oncol 7:e2100498, 2023.
Tumor specimens from diagnostic core biopsies from our ongoing phase II clinical trial (NCT04243616) of neoadjuvant chemotherapy and PD-1 inhibitor (cemiplimab; Regeneron Pharmaceuticals Inc) were used for these analyses
The authors.
National Center for Advancing Translational Sciences, National Institutes of Health Awards KL2TR001438.
L.N. Chaudhary: Other, Personal, Advisory Board: Puma Biotechnology, Seattle Genetics, Gilead Sciences, AstraZeneca, Novartis; Other, Institutional, Research Grant: Regeneron Pharmaceuticals. All other authors have declared no conflicts of interest.