Tumor-associated B-cells induce tumor heterogeneity and therapy resistance
View/ Open
Author
Somasundaram, Rajasekharan
Zhang, Gao
Fukunaga-Kalabis, Mizuho
Perego, Michela
Krepler, Clemens
Xu, Xiaowei
Wagner, Christine
Hristova, Denitsa
Zhang, Jie
Tian, Tian
Wei, Zhi
Liu, Qin
Garg, Kanika
Griss, Johannes
Hards, Rufus
Maurer, Margarita
Hafner, Christine
Mayerhöfer, Marius
Karanikas, Georgios
Jalili, Ahmad
Bauer-Pohl, Verena
Weihsengruber, Felix
Rappersberger, Klemens
Koller, Josef
Lang, Roland
Hudgens, Courtney
Chen, Guo
Tetzlaff, Michael
Wu, Lawrence
Frederick, Dennie Tompers
Scolyer, Richard A.
Long, Georgina V.
Damle, Manashree
Ellingsworth, Courtney
Grinman, Leon
Choi, Harry
Gavin, Brian J.
Dunagin, Margaret
Raj, Arjun
Scholler, Nathalie
Gross, Laura
Beqiri, Marilda
Bennett, Keiryn
Watson, Ian
Schaider, Helmut
Davies, Michael A.
Wargo, Jennifer
Czerniecki, Brian J.
Schuchter, Lynn
Herlyn, Dorothee
Herlyn, Meenhard
Wagner, Stephan N.
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.1038/s41467-017-00452-4Metadata
Show full item recordCitation
Somasundaram, R., G. Zhang, M. Fukunaga-Kalabis, M. Perego, C. Krepler, X. Xu, C. Wagner, et al. 2017. “Tumor-associated B-cells induce tumor heterogeneity and therapy resistance.” Nature Communications 8 (1): 607. doi:10.1038/s41467-017-00452-4. http://dx.doi.org/10.1038/s41467-017-00452-4.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605714/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:34491862
Collections
- HMS Scholarly Articles [17922]
Contact administrator regarding this item (to report mistakes or request changes)