TY - JOUR
T1 - Spatial interplay of lymphocytes and fibroblasts in estrogen receptor-positive HER2-negative breast cancer
AU - Nederlof, I.
AU - Hajizadeh, S.
AU - Sobhani, F.
AU - Raza, S. E. A.
AU - AbdulJabbar, K.
AU - Harkes, R.
AU - van de Vijver, M. J.
AU - Salgado, R.
AU - Desmedt, C.
AU - Kok, M.
AU - Yuan, Y.
AU - Horlings, H. M.
N1 - Funding Information: The authors thank all the many patients and families who contributed to this study, and all researchers, clinician, technicians, and administrative staff who have enabled this work to be carried out. Special thanks goes to the ICGC Breast Cancer Consortium for allowing us to access this dataset and use the valuable abundance of data. We thank all members of the Core Facility Molecular Pathology and Biobanking (CFMPB) from the Netherlands Cancer Institute for their help in sample preparation. Figure 1a, b, g were created with BioRender.com. This work was supported by funding from the Dutch Cancer Foundation (grant KWF-10510). Funding Information: The authors thank all the many patients and families who contributed to this study, and all researchers, clinician, technicians, and administrative staff who have enabled this work to be carried out. Special thanks goes to the ICGC Breast Cancer Consortium for allowing us to access this dataset and use the valuable abundance of data. We thank all members of the Core Facility Molecular Pathology and Biobanking (CFMPB) from the Netherlands Cancer Institute for their help in sample preparation. Figure were created with BioRender.com. This work was supported by funding from the Dutch Cancer Foundation (grant KWF-10510). Publisher Copyright: © 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - In estrogen-receptor-positive, HER2-negative (ER+HER2−) breast cancer, higher levels of tumor infiltrating lymphocytes (TILs) are often associated with a poor prognosis and this phenomenon is still poorly understood. Fibroblasts represent one of the most frequent cells in breast cancer and harbor immunomodulatory capabilities. Here, we evaluate the molecular and clinical impact of the spatial patterns of TILs and fibroblast in ER+HER2− breast cancer. We used a deep neural network to locate and identify tumor, TILs, and fibroblasts on hematoxylin and eosin-stained slides from 179 ER+HER2− breast tumors (ICGC cohort) together with a new density estimation analysis to measure the spatial patterns. We clustered tumors based on their spatial patterns and gene set enrichment analysis was performed to study their molecular characteristics. We independently assessed the spatial patterns in a second cohort of ER+HER2− breast cancer (N = 630, METABRIC) and studied their prognostic value. The spatial integration of fibroblasts, TILs, and tumor cells leads to a new reproducible spatial classification of ER+HER2− breast cancer and is linked to inflammation, fibroblast meddling, or immunosuppression. ER+HER2− patients with high TIL did not have a significant improved overall survival (HR = 0.76, P = 0.212), except when they had received chemotherapy (HR = 0.447). A poorer survival was observed for patients with high fibroblasts that did not show a high level of TILs (HR = 1.661, P = 0.0303). Especially spatial mixing of fibroblasts and TILs was associated with a good prognosis (HR = 0.464, P = 0.013). Our findings demonstrate a reproducible pipeline for the spatial profiling of TILs and fibroblasts in ER+HER2− breast cancer and suggest that this spatial interplay holds a decisive role in their cancer-immune interactions.
AB - In estrogen-receptor-positive, HER2-negative (ER+HER2−) breast cancer, higher levels of tumor infiltrating lymphocytes (TILs) are often associated with a poor prognosis and this phenomenon is still poorly understood. Fibroblasts represent one of the most frequent cells in breast cancer and harbor immunomodulatory capabilities. Here, we evaluate the molecular and clinical impact of the spatial patterns of TILs and fibroblast in ER+HER2− breast cancer. We used a deep neural network to locate and identify tumor, TILs, and fibroblasts on hematoxylin and eosin-stained slides from 179 ER+HER2− breast tumors (ICGC cohort) together with a new density estimation analysis to measure the spatial patterns. We clustered tumors based on their spatial patterns and gene set enrichment analysis was performed to study their molecular characteristics. We independently assessed the spatial patterns in a second cohort of ER+HER2− breast cancer (N = 630, METABRIC) and studied their prognostic value. The spatial integration of fibroblasts, TILs, and tumor cells leads to a new reproducible spatial classification of ER+HER2− breast cancer and is linked to inflammation, fibroblast meddling, or immunosuppression. ER+HER2− patients with high TIL did not have a significant improved overall survival (HR = 0.76, P = 0.212), except when they had received chemotherapy (HR = 0.447). A poorer survival was observed for patients with high fibroblasts that did not show a high level of TILs (HR = 1.661, P = 0.0303). Especially spatial mixing of fibroblasts and TILs was associated with a good prognosis (HR = 0.464, P = 0.013). Our findings demonstrate a reproducible pipeline for the spatial profiling of TILs and fibroblasts in ER+HER2− breast cancer and suggest that this spatial interplay holds a decisive role in their cancer-immune interactions.
UR - http://www.scopus.com/inward/record.url?scp=85128876993&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41523-022-00416-y
DO - https://doi.org/10.1038/s41523-022-00416-y
M3 - Article
C2 - 35484275
SN - 2374-4677
VL - 8
JO - NPJ Breast Cancer
JF - NPJ Breast Cancer
IS - 1
M1 - 56
ER -