Characteristics and Spatially Defined Immune (micro)landscapes of Early-stage PD-L1–positive Triple-negative Breast Cancer

Jodi M. Carter, Mei Yin C. Polley, Roberto A. Leon-Ferre, Jason Sinnwell, Kevin J. Thompson, Xue Wang, Yaohua Ma, David Zahrieh, Jennifer M. Kachergus, Malvika Solanki, Judy C. Boughey, Minetta C. Liu, James N. Ingle, Krishna R. Kalari, Fergus J. Couch, E. Aubrey Thompson, Matthew P. Goetz

Research output: Contribution to journalArticlepeer-review


Purpose: Programmed death ligand 1 [PD-(L)1]-targeted therapies have shown modest survival benefit in triple-negative breast cancer (TNBC). PD-L1þ 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 tumor–immune microenvironments (TIME) in early-stage PD-L1þ and PD-L1- TNBC. Experimental Design: From a large cohort of chemotherapy-na€ve TNBC, clinicopathologic features, deconvoluted RNA immune signatures, and intraepithelial and stromal TIME (Nanostring GeoMX) were identified in subsets of PD-L1þ and PD-L1- TNBC, as defined by FDA-approved PD-L1 companion assays. Results: 228 of 499 (46%) TNBC were PD-L1þ (SP142: ≥1% immune cells-positive). Using PD-L1 22C3, 46% had combined positive score (CPS) ≥ 1 and 16% had CPS ≥10. PD-L1þ TNBC were higher grade with higher tumor-infiltrating lymphocytes (TIL; P < 0.05). PD-L1 was not associated with improved survival following adjustment for TILs and other variables. RNA profiles of PD-L1þ TNBC had increased dendritic cell, macrophage, and T/B cell subset features; and decreased myeloid-derived suppressor cells. PD-L1þ stromal and intraepithelial TIMEs were highly enriched in IDO-1, HLA-DR, CD40, and CD163 compared with PD-L1-TIME, with spatially specific alterations in CTLA-4, Stimulator of Interferon Genes (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-L1þ (SP142 companion assay) while 16% were PD-L1þ with the 22C3 companion assay. PD-L1þ TNBC had specific myeloid-derived and lymphoid features. Spatially defined PD-L1þ TIME were enriched in several clinically actionable immune proteins. These data may inform future studies on combinatorial immunotherapies for patients with PD-L1þ TNBC.

Original languageEnglish (US)
Pages (from-to)5628-5637
Number of pages10
JournalClinical Cancer Research
Issue number20
StatePublished - Oct 15 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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