Tumor-associated B-cells induce tumor heterogeneity and therapy resistance

Rajasekharan Somasundaram (), Gao Zhang, Mizuho Fukunaga-Kalabis, Michela Perego, Clemens Krepler, Xiaowei Xu, Christine Wagner, Denitsa Hristova, Jie Zhang, Tian Tian, Zhi Wei, Qin Liu, Kanika Garg, Johannes Griss, Rufus Hards, Margarita Maurer, Christine Hafner, Marius Mayerhöfer, Georgios Karanikas, Ahmad Jalili, Verena Bauer-Pohl, Felix Weihsengruber, Klemens Rappersberger, Josef Koller, Roland Lang, Courtney Hudgens, Guo Chen, Michael Tetzlaff, Lawrence Wu, Dennie Tompers Frederick, Richard A. Scolyer, Georgina V. Long, Manashree Damle, Courtney Ellingsworth, Leon Grinman, Harry Choi, Brian J. Gavin, Margaret Dunagin, Arjun Raj, Nathalie Scholler, Laura Gross, Marilda Beqiri, Keiryn Bennett, Ian Watson, Helmut Schaider, Michael A. Davies, Jennifer Wargo, Brian J. Czerniecki, Lynn Schuchter, Dorothee Herlyn, Keith Flaherty, Meenhard Herlyn () and Stephan N. Wagner ()
Additional contact information
Rajasekharan Somasundaram: The Wistar Institute
Gao Zhang: The Wistar Institute
Mizuho Fukunaga-Kalabis: The Wistar Institute
Michela Perego: The Wistar Institute
Clemens Krepler: The Wistar Institute
Xiaowei Xu: University of Pennsylvania
Christine Wagner: Medical University of Vienna
Denitsa Hristova: The Wistar Institute
Jie Zhang: New Jersey Institute of Technology
Tian Tian: New Jersey Institute of Technology
Zhi Wei: New Jersey Institute of Technology
Qin Liu: The Wistar Institute
Kanika Garg: Medical University of Vienna
Johannes Griss: Medical University of Vienna
Rufus Hards: The Wistar Institute
Margarita Maurer: Medical University of Vienna
Christine Hafner: Karl Landsteiner University of Health Sciences
Marius Mayerhöfer: Medical University of Vienna
Georgios Karanikas: Medical University of Vienna
Ahmad Jalili: Medical University of Vienna
Verena Bauer-Pohl: Medical University of Vienna
Felix Weihsengruber: Teaching Hospital of the Medical University Vienna
Klemens Rappersberger: Teaching Hospital of the Medical University Vienna
Josef Koller: Paracelsus Medical University Salzburg
Roland Lang: Paracelsus Medical University Salzburg
Courtney Hudgens: The University of Texas MD Anderson Cancer Center
Guo Chen: The University of Texas MD Anderson Cancer Center
Michael Tetzlaff: The University of Texas MD Anderson Cancer Center
Lawrence Wu: The Wistar Institute
Dennie Tompers Frederick: Harvard Medical School
Richard A. Scolyer: and The University of Sydney
Georgina V. Long: and The University of Sydney
Manashree Damle: The Wistar Institute
Courtney Ellingsworth: The Wistar Institute
Leon Grinman: The Wistar Institute
Harry Choi: The Wistar Institute
Brian J. Gavin: The Wistar Institute
Margaret Dunagin: University of Pennsylvania
Arjun Raj: University of Pennsylvania
Nathalie Scholler: Hospital of University of Pennsylvania
Laura Gross: The Wistar Institute
Marilda Beqiri: The Wistar Institute
Keiryn Bennett: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Ian Watson: McGill University
Helmut Schaider: University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute
Michael A. Davies: The University of Texas MD Anderson Cancer Center
Jennifer Wargo: The University of Texas MD Anderson Cancer, Center
Brian J. Czerniecki: Hospital of University of Pennsylvania
Lynn Schuchter: Hospital of University of Pennsylvania
Dorothee Herlyn: The Wistar Institute
Keith Flaherty: Harvard Medical School
Meenhard Herlyn: The Wistar Institute
Stephan N. Wagner: Medical University of Vienna

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract In melanoma, therapies with inhibitors to oncogenic BRAFV600E are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations. We describe here a mechanism of acquired drug resistance through the tumor microenvironment, which is mediated by human tumor-associated B cells. Human melanoma cells constitutively produce the growth factor FGF-2, which activates tumor-infiltrating B cells to produce the growth factor IGF-1. B-cell-derived IGF-1 is critical for resistance of melanomas to BRAF and MEK inhibitors due to emergence of heterogeneous subpopulations and activation of FGFR-3. Consistently, resistance of melanomas to BRAF and/or MEK inhibitors is associated with increased CD20 and IGF-1 transcript levels in tumors and IGF-1 expression in tumor-associated B cells. Furthermore, first clinical data from a pilot trial in therapy-resistant metastatic melanoma patients show anti-tumor activity through B-cell depletion by anti-CD20 antibody. Our findings establish a mechanism of acquired therapy resistance through tumor-associated B cells with important clinical implications.

Date: 2017
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DOI: 10.1038/s41467-017-00452-4

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