Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments
Kester, Lennart; Seinstra, Danielle; van Rossum, Annelot G.J.; Vennin, Claire; Hoogstraat, Marlous; van der Velden, Daphne; Opdam, Mark; van Werkhoven, Erik; Hahn, Kerstin; Nederlof, Iris; Lips, Ester H.; Mandjes, Ingrid A.M.; van Leeuwen-Stok, A. Elise; Canisius, Sander; van Tinteren, Harm; Imholz, Alex L.T.; Portielje, Johanneke E.A.; Bos, Monique E.M.M.; Bakker, Sandra D.; Rutgers, Emiel J.; Horlings, Hugo M.; Wesseling, Jelle; Voest, Emile E.; Wessels, Lodewyk F.A.; Kok, Marleen; Oosterkamp, Hendrika M.; van Oudenaarden, Alexander; Linn, Sabine C.; van Rheenen, Jacco
(2022) Clinical Cancer Research, volume 28, issue 5, pp. 960 - 971
(Article)
Abstract
Purpose: Extensive work in preclinical models has shown that microenvironmental cells influence many aspects of cancer cell behavior, including metastatic potential and their sensitivity to therapeutics. In the human setting, this behavior is mainly correlated with the presence of immune cells. Here, in addition to T cells, B cells, macrophages,
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and mast cells, we identified the relevance of nonimmune cell types for breast cancer survival and therapy benefit, including fibroblasts, myoepithelial cells, muscle cells, endothelial cells, and seven distinct epithelial cell types. Experimental Design: Using single-cell sequencing data, we generated reference profiles for all these cell types. We used these reference profiles in deconvolution algorithms to optimally detangle the cellular composition of more than 3,500 primary breast tumors of patients that were enrolled in the SCAN-B and MATADOR clinical trials, and for which bulk mRNA sequencing data were available. Results: This large data set enables us to identify and subsequently validate the cellular composition of microenvironments that distinguish differential survival and treatment benefit for different treatment regimens in patients with primary breast cancer. In addition to immune cells, we have identified that survival and therapy benefit are characterized by various contributions of distinct epithelial cell types. Conclusions: From our study, we conclude that differential survival and therapy benefit of patients with breast cancer are characterized by distinct microenvironments that include specific populations of immune and epithelial cells.
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Keywords: Oncology, Cancer Research
ISSN: 1078-0432
Publisher: American Association for Cancer Research Inc.
Note: Funding Information: L. Kester reports a patent for “Method for determining cellular composition of a tumor” (18020578.3) pending. E.H. Lips reports grants from CRUK/KWF outside the submitted work. A.E. van Leeuwen-Stok reports grants from Roche, Novartis, Philips, Servier, and Agendia outside the submitted work. M.E.M.M. Bos is on the advisory board at AstraZeneca on Trastuzumab-deruxtecan (Europe). H.M. Horlings reports other support from Roche Diagnostics BV during the conduct of the study. J. Wesseling reports research not related to the research presented in this manuscript as funded by Cancer Research UK, KWF Dutch Cancer Society ZonMW, and the Antoni van Leeuwenhoek Foundation. E.E. Voest reports grants from Roche, Pfizer, Clovis, Novartis, AstraZeneca, BMS, Eli Lilly, MSD, Amgen, Bayer, and Sanofi outside the submitted work. L.F.A. Wessels reports grants from Genmab BV during the conduct of the study. M. Kok reports grants from BMS, Roche, and AstraZeneca, as well as other support from Daiichi outside the submitted work. H.M. Oosterkamp reports grants from Amgen, Sanofi, and Dutch Cancer Society during the conduct of the study, as well as personal fees from Roche, MSD, Daiichi, AstraZeneca, Lilly, and Pfizer outside the submitted work. S.C. Linn reports grants from Amgen, Sanofi, and Dutch Cancer Society during the conduct of the study. S.C. Linn also reports grants and nonfinancial support from AstraZeneca, Genentech/Roche, Tesaro (now owned by GSK), and Immunomedics; grants from Eurocept-pharmaceuticals, Novartis, and Pfizer; and other support from Cergentis, IBM, Daiichi Sankyo, and Bayer outside the submitted work. J. van Rheenen reports a patent for “Method for determining cellular composition of a tumor” (18020578.3) pending. No disclosures were reported by the other authors. Funding Information: First, we would like to thank all patients and their families that were included in this study. Also, we would like to express our gratitude to the study teams of the participating centers, the Data Center of the Netherlands Cancer Institute for collecting the data, the Core Facility – Molecular Pathology and Biobanking of the Netherlands Cancer Institute for their help with the immunohistochemistry stainings, the Genomics Core Facility of the Netherlands Cancer Institute for their work on the RNA sequencing, the Hubrecht and NKI FACS facility, and the Dutch Breast Cancer Research Group (BOOG) for their role in coordinating the study. This work was supported by CancerGenomics.nl (Netherlands Organization for Scientific Research) program (to J. van Rheenen) and the Josef Steiner Cancer Research Foundation (to J. van Rheenen). The MATADOR trial was funded by the Dutch Cancer Society (CKTO 2004–04) and by unrestricted institutional research grants from Sanofi and Amgen (to S.C. Linn and H.M. Oosterkamp). C. Vennin was supported by a fellowship from the Human Frontiers in Science Program (LT000082/2018-L3). Publisher Copyright: © 2021 The Authors.
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