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; Stephan N Wagner

doi:10.1038/s41467-017-00452-4

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 JaliliVerena 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

Division of Dermatology and Venereology (University Hospital St. Pölten)

Research output: Journal article (peer-reviewed) › Journal article

109 Citations (Scopus)

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.

Original language	English
Article number	607
Pages (from-to)	607
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00452-4
Publication status	Published - 01 Dec 2017

Keywords

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
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
Tumor Microenvironment

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry,Genetics and Molecular Biology

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10.1038/s41467-017-00452-4

Cite this

Somasundaram, R., Zhang, G., Fukunaga-Kalabis, M., Perego, M., Krepler, C., Xu, X., Wagner, C., Hristova, D., Zhang, J., Tian, T., Wei, Z., Liu, Q., Garg, K., Griss, J., Hards, R., Maurer, M., Hafner, C., Mayerhöfer, M., Karanikas, G., ... Wagner, S. N. (2017). Tumor-associated B-cells induce tumor heterogeneity and therapy resistance. Nature Communications, 8(1), 607. Article 607. https://doi.org/10.1038/s41467-017-00452-4

@article{06822156e816429bae563abfb7183482,

title = "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.",

keywords = "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, 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, Tumor Microenvironment",

author = "Rajasekharan Somasundaram and Gao Zhang and Mizuho Fukunaga-Kalabis and Michela Perego and Clemens Krepler and Xiaowei Xu and Christine Wagner and Denitsa Hristova and Jie Zhang and Tian Tian and Zhi Wei and Qin Liu and Kanika Garg and Johannes Griss and Rufus Hards and Margarita Maurer and Christine Hafner and Marius Mayerh{\"o}fer and Georgios Karanikas and Ahmad Jalili and Verena Bauer-Pohl and Felix Weihsengruber and Klemens Rappersberger and Josef Koller and Roland Lang and Courtney Hudgens and Guo Chen and Michael Tetzlaff and Lawrence Wu and Frederick, {Dennie Tompers} and Scolyer, {Richard A} and Long, {Georgina V} and Manashree Damle and Courtney Ellingsworth and Leon Grinman and Harry Choi and Gavin, {Brian J} and Margaret Dunagin and Arjun Raj and Nathalie Scholler and Laura Gross and Marilda Beqiri and Keiryn Bennett and Ian Watson and Helmut Schaider and Davies, {Michael A} and Jennifer Wargo and Czerniecki, {Brian J} and Lynn Schuchter and Dorothee Herlyn and Keith Flaherty and Meenhard Herlyn and Wagner, {Stephan N}",

note = "Funding Information: We thank Drs. Dmitry Gabrilovich and Jose R. Conejo-Garcia for their valuable suggestions. We thank Peter Petzelbauer (Medical University of Vienna, Vienna, Austria) for providing melanoma TMAs. We thank F. Keeney and J. Hayden (Wistar Imaging Facility); J. Faust and D. Ambrose (Wistar Flow-Cytometry); D. Schultz (Molecular Screening Facility) for technical support and P. Wickramasinghe (Centre for systems and computational Biology) for computational biology support. We thank F. Trautinger (University of Health Sciences, St. P{\"o}lten, Austria), U. J{\"a}ger und W. Pickl (both Medical University of Vienna) for serving on the DSMB, and J. Pleiner-Duxneuner, M. Wolzt, and the members of the Academic Clinical Studies Support Office of the Medical University of Vienna for managing the clinical trial. We thank Thomas Bogenrieder, Sophie Nagler, and Hardo F. Fischer for support during their time at GSK. The research was funded by NIH grants CA 114046, CA 025874, CA 047159, CA174523, and CA 010815; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation;the Vienna Hans Mayr-Fund and the Vienna Science and Technology Fund (WWTF through project LS11-045 to Stephan N. Wagner). Support from colleagues at Melanoma Institute Australia and the Australian National Health and Medical Research Council and Cancer Institute New South Wales is also gratefully acknowledged. Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-00452-4",

language = "English",

volume = "8",

pages = "607",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Somasundaram, R, Zhang, G, Fukunaga-Kalabis, M, Perego, M, Krepler, C, Xu, X, Wagner, C, Hristova, D, Zhang, J, Tian, T, Wei, Z, Liu, Q, Garg, K, Griss, J, Hards, R, Maurer, M, Hafner, C, Mayerhöfer, M, Karanikas, G, Jalili, A, Bauer-Pohl, V, Weihsengruber, F, Rappersberger, K, Koller, J, Lang, R, Hudgens, C, Chen, G, Tetzlaff, M, Wu, L, Frederick, DT, Scolyer, RA, Long, GV, Damle, M, Ellingsworth, C, Grinman, L, Choi, H, Gavin, BJ, Dunagin, M, Raj, A, Scholler, N, Gross, L, Beqiri, M, Bennett, K, Watson, I, Schaider, H, Davies, MA, Wargo, J, Czerniecki, BJ, Schuchter, L, Herlyn, D, Flaherty, K, Herlyn, M & Wagner, SN 2017, 'Tumor-associated B-cells induce tumor heterogeneity and therapy resistance', Nature Communications, vol. 8, no. 1, 607, pp. 607. https://doi.org/10.1038/s41467-017-00452-4

TY - JOUR

T1 - Tumor-associated B-cells induce tumor heterogeneity and therapy resistance

AU - Somasundaram, Rajasekharan

AU - Zhang, Gao

AU - Fukunaga-Kalabis, Mizuho

AU - Perego, Michela

AU - Krepler, Clemens

AU - Xu, Xiaowei

AU - Wagner, Christine

AU - Hristova, Denitsa

AU - Zhang, Jie

AU - Tian, Tian

AU - Wei, Zhi

AU - Liu, Qin

AU - Garg, Kanika

AU - Griss, Johannes

AU - Hards, Rufus

AU - Maurer, Margarita

AU - Hafner, Christine

AU - Mayerhöfer, Marius

AU - Karanikas, Georgios

AU - Jalili, Ahmad

AU - Bauer-Pohl, Verena

AU - Weihsengruber, Felix

AU - Rappersberger, Klemens

AU - Koller, Josef

AU - Lang, Roland

AU - Hudgens, Courtney

AU - Chen, Guo

AU - Tetzlaff, Michael

AU - Wu, Lawrence

AU - Frederick, Dennie Tompers

AU - Scolyer, Richard A

AU - Long, Georgina V

AU - Damle, Manashree

AU - Ellingsworth, Courtney

AU - Grinman, Leon

AU - Choi, Harry

AU - Gavin, Brian J

AU - Dunagin, Margaret

AU - Raj, Arjun

AU - Scholler, Nathalie

AU - Gross, Laura

AU - Beqiri, Marilda

AU - Bennett, Keiryn

AU - Watson, Ian

AU - Schaider, Helmut

AU - Davies, Michael A

AU - Wargo, Jennifer

AU - Czerniecki, Brian J

AU - Schuchter, Lynn

AU - Herlyn, Dorothee

AU - Flaherty, Keith

AU - Herlyn, Meenhard

AU - Wagner, Stephan N

N1 - Funding Information: We thank Drs. Dmitry Gabrilovich and Jose R. Conejo-Garcia for their valuable suggestions. We thank Peter Petzelbauer (Medical University of Vienna, Vienna, Austria) for providing melanoma TMAs. We thank F. Keeney and J. Hayden (Wistar Imaging Facility); J. Faust and D. Ambrose (Wistar Flow-Cytometry); D. Schultz (Molecular Screening Facility) for technical support and P. Wickramasinghe (Centre for systems and computational Biology) for computational biology support. We thank F. Trautinger (University of Health Sciences, St. Pölten, Austria), U. Jäger und W. Pickl (both Medical University of Vienna) for serving on the DSMB, and J. Pleiner-Duxneuner, M. Wolzt, and the members of the Academic Clinical Studies Support Office of the Medical University of Vienna for managing the clinical trial. We thank Thomas Bogenrieder, Sophie Nagler, and Hardo F. Fischer for support during their time at GSK. The research was funded by NIH grants CA 114046, CA 025874, CA 047159, CA174523, and CA 010815; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation;the Vienna Hans Mayr-Fund and the Vienna Science and Technology Fund (WWTF through project LS11-045 to Stephan N. Wagner). Support from colleagues at Melanoma Institute Australia and the Australian National Health and Medical Research Council and Cancer Institute New South Wales is also gratefully acknowledged. Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - Antibodies, Monoclonal/therapeutic use

KW - Antibodies, Monoclonal, Humanized

KW - Antineoplastic Agents/therapeutic use

KW - B-Lymphocytes/metabolism

KW - Cell Survival

KW - Cisplatin/therapeutic use

KW - Drug Resistance, Neoplasm

KW - Fibroblast Growth Factor 2/metabolism

KW - Humans

KW - In Vitro Techniques

KW - Insulin-Like Growth Factor I/metabolism

KW - Lymphocytes, Tumor-Infiltrating/metabolism

KW - Melanoma/drug therapy

KW - Paclitaxel/therapeutic use

KW - Pilot Projects

KW - Protein Kinase Inhibitors/therapeutic use

KW - Proto-Oncogene Proteins B-raf/genetics

KW - Receptor, Fibroblast Growth Factor, Type 3/metabolism

KW - Skin Neoplasms/drug therapy

KW - Tumor Microenvironment

UR - http://www.scopus.com/inward/record.url?scp=85029869610&partnerID=8YFLogxK

U2 - 10.1038/s41467-017-00452-4

DO - 10.1038/s41467-017-00452-4

M3 - Journal article

C2 - 28928360

SN - 2041-1723

VL - 8

SP - 607

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 607

ER -

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

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Keywords

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