PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas

Abstract

Programmed death ligand 1 (PD-L1) expression by tumor-infiltrating lymphocytes (TILs) and tumor cells in breast cancer has been reported, but the relationships between PD-L1 expression by TIL, carcinoma cells, and other immunologic features of the breast tumor microenvironment remain unclear. We therefore evaluated the interrelationships between tumor cell surface and TIL PD-L1 expression, lymphocyte subpopulations, and patterns of immune cell infiltration in cohorts of treatment-naive, primary breast cancers (PBCs) (n = 45) and matched PBC and metastatic breast cancers (MBC) (n = 26). Seventy-eight percent of untreated PBCs contained PD-L1(+) TILs, but only 21% had PD-L1(+) carcinoma cells. Carcinoma PD-L1 expression localized to the tumor invasive front and was associated with high tumor grade (P = .04). Eighty-nine percent of PD-L1(+) carcinomas contained brisk TIL infiltrates, compared to only 24% of PD-L1(-) carcinomas; this included CD3(+) (P = .02), CD4(+) (P = .04), CD8(+) (P = .002), and FoxP3(+) T cells (P = .02). PD-L1(+) PBCs were more likely to contain PD-L1(+) TIL than PD-L1(-) PBCs (P = .04). Peripheral lymphoid aggregates were present in 100% of PD-L1(+) compared to 41% of PD-L1(-) PBC (P < .001). No patient with PD-L1(+) PBC developed distant recurrence, compared to 15% of patients with PD-L1(-) PBC. For the matched PBC and MBC cohort, 2 patients (8%) had PD-L1(+) tumors, with 1 case concordant and 1 case discordant for carcinoma PD-L1 expression in the PBC and MBC. Our data support PD-L1 expression by tumor cells as a biomarker of active breast tumor immunity and programmed death 1 blockade as a therapeutic strategy for breast cancer.

Keywords: Metastatic breast cancer; PD-L1; Primary breast cancer; Tumor infiltrating lymphocytes; Tumor microenvironment.

Fig. 1

Immunologic features of the primary breast carcinoma (PBC) tumor microenvironment. Tumor-infiltrating CD3+ T lymphocytes (A) and CD20+ B lymphocytes (B) are preferentially located at the peritumoral interface with the surrounding stroma. Lymphoid aggregates were seen in 53% of PBCs, including 100% of PD-L1⁺ carcinomas (C). The cellular composition of lymphoid aggregates in the PBCs shows scattered PD-L1⁺ lymphocytes (D), CD3⁺ T lymphocytes (E), and CD20⁺ B lymphocytes (F). PD-L1 expression by carcinoma cells was seen in 21% of treatment-naive PBCs (G). All PD-L1⁺ invasive PBCs with associated ductal carcinoma in situ (DCIS) showed PD-L1 expression by carcinoma cell within the DCIS (H).

Fig. 2

Carcinoma PD-L1 expression in a patient with metastatic breast carcinoma. This patient's triple-negative primary breast carcinoma (A, H&E) was PD-L1⁻ (B), but the lung metastasis (C, H&E) was PD-L1⁺ (D).