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

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.Resistance to BRAFV600E inhibitors often occurs in melanoma patients. Here, the authors describe a potential mechanism of acquired drug resistance mediated by tumor-associated B cells-derived IGF-1.

• Authors: 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, Stephan N Wagner
• Journal: Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 607 (09 19 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 28928360 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• IGF1 protein, human
• Protein Kinase Inhibitors
• Fibroblast Growth Factor 2
• Insulin-Like Growth Factor I
• FGFR3 protein, human
• Receptor, Fibroblast Growth Factor, Type 3
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• ofatumumab
• Paclitaxel
• Cisplatin

Topics

• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (therapeutic use)
• B-Lymphocytes (metabolism)
• Cell Survival
• Cisplatin (therapeutic use)
• Drug Resistance, Neoplasm
• Fibroblast Growth Factor 2 (metabolism)
• Humans
• In Vitro Techniques
• Insulin-Like Growth Factor I (metabolism)
• Lymphocytes, Tumor-Infiltrating (metabolism)
• Melanoma (drug therapy, genetics)
• Paclitaxel (therapeutic use)
• Pilot Projects
• Protein Kinase Inhibitors (therapeutic use)
• Proto-Oncogene Proteins B-raf (genetics)
• Receptor, Fibroblast Growth Factor, Type 3 (metabolism)
• Skin Neoplasms (drug therapy, genetics)
• Tumor Microenvironment