Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression

A Calcinotto, A Brevi, M Chesi, R Ferrarese, L Garcia Perez, M Grioni, S Kumar, VM Garbitt, ME Sharik, KJ Henderson, G Tonon, M Tomura, Y Miwa, E Esplugues, RA Flavell, S Huber, F Canducci, VS Rajkumar, PL Bergsagel, M Bellone

Research output: Contribution to journalArticle

Abstract

The gut microbiota has been causally linked to cancer, yet how intestinal microbes influence progression of extramucosal tumors is poorly understood. Here we provide evidence implying that Prevotella heparinolytica promotes the differentiation of Th17 cells colonizing the gut and migrating to the bone marrow (BM) of transgenic Vk*MYC mice, where they favor progression of multiple myeloma (MM). Lack of IL-17 in Vk*MYC mice, or disturbance of their microbiome delayed MM appearance. Similarly, in smoldering MM patients, higher levels of BM IL-17 predicted faster disease progression. IL-17 induced STAT3 phosphorylation in murine plasma cells, and activated eosinophils. Treatment of Vk*MYC mice with antibodies blocking IL-17, IL-17RA, and IL-5 reduced BM accumulation of Th17 cells and eosinophils and delayed disease progression. Thus, in Vk*MYC mice, commensal bacteria appear to unleash a paracrine signaling network between adaptive and innate immunity that accelerates progression to MM, and can be targeted by already available therapies. © 2018, The Author(s).
Original languageEnglish
Article number4832
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 2018

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eosinophils
interleukins
Interleukin-17
Microbiota
Multiple Myeloma
Eosinophils
progressions
mice
bone marrow
Th17 Cells
Bone
Bone Marrow
cells
Disease Progression
Paracrine Communication
Prevotella
Intestinal Neoplasms
Phosphorylation
smoldering
Blocking Antibodies

Cite this

Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression. / Calcinotto, A; Brevi, A; Chesi, M; Ferrarese, R; Garcia Perez, L; Grioni, M; Kumar, S; Garbitt, VM; Sharik, ME; Henderson, KJ; Tonon, G; Tomura, M; Miwa, Y; Esplugues, E; Flavell, RA; Huber, S; Canducci, F; Rajkumar, VS; Bergsagel, PL; Bellone, M.

In: Nature Communications, Vol. 9, 4832, 2018.

Research output: Contribution to journalArticle

Calcinotto, A, Brevi, A, Chesi, M, Ferrarese, R, Garcia Perez, L, Grioni, M, Kumar, S, Garbitt, VM, Sharik, ME, Henderson, KJ, Tonon, G, Tomura, M, Miwa, Y, Esplugues, E, Flavell, RA, Huber, S, Canducci, F, Rajkumar, VS, Bergsagel, PL & Bellone, M 2018, 'Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression', Nature Communications, vol. 9, 4832. https://doi.org/10.1038/s41467-018-07305-8
Calcinotto, A ; Brevi, A ; Chesi, M ; Ferrarese, R ; Garcia Perez, L ; Grioni, M ; Kumar, S ; Garbitt, VM ; Sharik, ME ; Henderson, KJ ; Tonon, G ; Tomura, M ; Miwa, Y ; Esplugues, E ; Flavell, RA ; Huber, S ; Canducci, F ; Rajkumar, VS ; Bergsagel, PL ; Bellone, M. / Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression. In: Nature Communications. 2018 ; Vol. 9.
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abstract = "The gut microbiota has been causally linked to cancer, yet how intestinal microbes influence progression of extramucosal tumors is poorly understood. Here we provide evidence implying that Prevotella heparinolytica promotes the differentiation of Th17 cells colonizing the gut and migrating to the bone marrow (BM) of transgenic Vk*MYC mice, where they favor progression of multiple myeloma (MM). Lack of IL-17 in Vk*MYC mice, or disturbance of their microbiome delayed MM appearance. Similarly, in smoldering MM patients, higher levels of BM IL-17 predicted faster disease progression. IL-17 induced STAT3 phosphorylation in murine plasma cells, and activated eosinophils. Treatment of Vk*MYC mice with antibodies blocking IL-17, IL-17RA, and IL-5 reduced BM accumulation of Th17 cells and eosinophils and delayed disease progression. Thus, in Vk*MYC mice, commensal bacteria appear to unleash a paracrine signaling network between adaptive and innate immunity that accelerates progression to MM, and can be targeted by already available therapies. {\circledC} 2018, The Author(s).",
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T1 - Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression

AU - Calcinotto, A

AU - Brevi, A

AU - Chesi, M

AU - Ferrarese, R

AU - Garcia Perez, L

AU - Grioni, M

AU - Kumar, S

AU - Garbitt, VM

AU - Sharik, ME

AU - Henderson, KJ

AU - Tonon, G

AU - Tomura, M

AU - Miwa, Y

AU - Esplugues, E

AU - Flavell, RA

AU - Huber, S

AU - Canducci, F

AU - Rajkumar, VS

AU - Bergsagel, PL

AU - Bellone, M

PY - 2018

Y1 - 2018

N2 - The gut microbiota has been causally linked to cancer, yet how intestinal microbes influence progression of extramucosal tumors is poorly understood. Here we provide evidence implying that Prevotella heparinolytica promotes the differentiation of Th17 cells colonizing the gut and migrating to the bone marrow (BM) of transgenic Vk*MYC mice, where they favor progression of multiple myeloma (MM). Lack of IL-17 in Vk*MYC mice, or disturbance of their microbiome delayed MM appearance. Similarly, in smoldering MM patients, higher levels of BM IL-17 predicted faster disease progression. IL-17 induced STAT3 phosphorylation in murine plasma cells, and activated eosinophils. Treatment of Vk*MYC mice with antibodies blocking IL-17, IL-17RA, and IL-5 reduced BM accumulation of Th17 cells and eosinophils and delayed disease progression. Thus, in Vk*MYC mice, commensal bacteria appear to unleash a paracrine signaling network between adaptive and innate immunity that accelerates progression to MM, and can be targeted by already available therapies. © 2018, The Author(s).

AB - The gut microbiota has been causally linked to cancer, yet how intestinal microbes influence progression of extramucosal tumors is poorly understood. Here we provide evidence implying that Prevotella heparinolytica promotes the differentiation of Th17 cells colonizing the gut and migrating to the bone marrow (BM) of transgenic Vk*MYC mice, where they favor progression of multiple myeloma (MM). Lack of IL-17 in Vk*MYC mice, or disturbance of their microbiome delayed MM appearance. Similarly, in smoldering MM patients, higher levels of BM IL-17 predicted faster disease progression. IL-17 induced STAT3 phosphorylation in murine plasma cells, and activated eosinophils. Treatment of Vk*MYC mice with antibodies blocking IL-17, IL-17RA, and IL-5 reduced BM accumulation of Th17 cells and eosinophils and delayed disease progression. Thus, in Vk*MYC mice, commensal bacteria appear to unleash a paracrine signaling network between adaptive and innate immunity that accelerates progression to MM, and can be targeted by already available therapies. © 2018, The Author(s).

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M3 - Article

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