Characteristics and spatially-defined immune (micro)landscapes of early-stage PD-L1-positive triple-negative breast cancer
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PURPOSE: PD-(L)1-targeted therapies have shown modest survival benefit in triple-negative breast cancer (TNBC). PD-L1+ microenvironments in TNBC are not well-characterized and may inform combinatorial immune therapies. Herein, we characterized clinicopathologic features, RNA-based immune signatures and spatially-defined protein-based immune microenvironments (TIME) in early-stage PD-L1+ and PD-L1- TNBC. EXPERIMENTAL DESIGN: From a large cohort of chemotherapy-naive TNBC, clinicopathologic features, deconvoluted RNA immune signatures, and intraepithelial and stromal TIME (Nanostring GeoMX(TM)) were identified in subsets of PD-L1+ and PD-L1- TNBC, as defined by FDA-approved PD-L1 companion assays. RESULTS: 228/499 (46%) TNBC were PD-L1+ (SP142: {greater than or equal to}1% immune cells-positive). Using PD-L1 22C3, 46% had combined positive score (CPS) {greater than or equal to} 1 and 16% had CPS {greater than or equal to}10. PD-L1+ TNBC were higher grade with higher TILs (p <0.05). PD-L1 was not associated with improved survival following adjustment for TILs and other variables. RNA profiles of PD-L1+ TNBC had increased dendritic cell, macrophages and T/B cell subset features; and decreased myeloid-derived suppressor cells. PD-L1+ stromal and intraepithelial TIME were highly enriched in IDO-1, HLA-DR, CD40 and CD163 compared to PD-L1- TIME, with spatially-specific alterations in CTLA-4, STING, and fibronectin. Macrophage and antigen presentation-related proteins correlated most strongly with PD-L1 protein. CONCLUSIONS: In this early-stage TNBC cohort, nearly 50% were PD-L1+ (SP142 companion assay) while 16% were PD-L1+ with the 22C3 companion assay. PD-L1+ TNBC had specific myeloid-derived and lymphoid features. Spatially-defined PD-L1+TIME were enriched in several clinically-actionable immune proteins. These data may inform future studies on combinatorial immunotherapies for patients with PD-L1+ TNBC.
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