TY - JOUR
T1 - Characteristics and Spatially Defined Immune (micro)landscapes of Early-stage PD-L1–positive Triple-negative Breast Cancer
AU - Carter, Jodi M.
AU - Polley, Mei Yin C.
AU - Leon-Ferre, Roberto A.
AU - Sinnwell, Jason
AU - Thompson, Kevin J.
AU - Wang, Xue
AU - Ma, Yaohua
AU - Zahrieh, David
AU - Kachergus, Jennifer M.
AU - Solanki, Malvika
AU - Boughey, Judy C.
AU - Liu, Minetta C.
AU - Ingle, James N.
AU - Kalari, Krishna R.
AU - Couch, Fergus J.
AU - Thompson, E. Aubrey
AU - Goetz, Matthew P.
N1 - Publisher Copyright:
©2021 The Authors; Published by the American Association for Cancer Research
PY - 2021/10/15
Y1 - 2021/10/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-21-0343
DO - 10.1158/1078-0432.CCR-21-0343
M3 - Article
C2 - 34108182
AN - SCOPUS:85114246004
SN - 1078-0432
VL - 27
SP - 5628
EP - 5637
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 20
ER -