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 - Funding Information:
J.M. Carter reports personal fees from Roche; and personal fees from Merck outside the submitted work. R.A. Leon-Ferre reports non-financial support from Immunomedics during the conduct of the study; and other support from AstraZeneca outside the submitted work. J.C. Boughey reports grants from Lilly outside the submitted work. J.N. Ingle reports grants from NIH during the conduct of the study. M.P. Goetz reports other support from Eagle Pharmaceuticals, Lilly, Biovica, Novartis, Sermonix, Context Therapeutics, Pfizer, Biotheranostics, AstraZeneca; grants from Pfizer, Sermonix; and grants from Lilly outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
This work was supported by a grant from the NIH [P50CA116201: Mayo Clinic Breast Specialized Program of Research Excellence (SPORE), to J.M. Carter, M.-Y.C. Polley, K.R. Kalari, D. Zahrieh, J.N. Ingle, and M.P. Goetz], and the Breast Cancer Research Foundation (BCRF-19–161, to E.A. Thompson).
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
VL - 27
SP - 5628
EP - 5637
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 20
ER -