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

Research output: Contribution to journal › Article › peer-review

104 Scopus citations

Abstract

In melanoma, therapies with inhibitors to oncogenic BRAF^V600E 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.

Original language	English (US)
Article number	607
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00452-4
State	Published - Dec 1 2017

ASJC Scopus subject areas

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

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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), Article 607. https://doi.org/10.1038/s41467-017-00452-4

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. https://doi.org/10.1038/s41467-017-00452-4

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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.",

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.}",

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

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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.

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.

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.

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VL - 8

JO - Nature communications

JF - Nature communications

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

Abstract

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