TY - JOUR
T1 - Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression
AU - Calcinotto, Arianna
AU - Brevi, Arianna
AU - Chesi, Marta
AU - Ferrarese, Roberto
AU - Garcia Perez, Laura
AU - Grioni, Matteo
AU - Kumar, Shaji
AU - Garbitt, Victoria M.
AU - Sharik, Meaghen E.
AU - Henderson, Kimberly J.
AU - Tonon, Giovanni
AU - Tomura, Michio
AU - Miwa, Yoshihiro
AU - Esplugues, Enric
AU - Flavell, Richard A.
AU - Huber, Samuel
AU - Canducci, Filippo
AU - Rajkumar, Vincent S.
AU - Bergsagel, P. Leif
AU - Bellone, Matteo
N1 - Funding Information:
We are indebted to Yoichiro Iwakura (Institute of Medical Science, Tokio, Japan) and William R. Heath (University of Melbourne, Parkville, Victoria, Australia) for providing us IL-17KO and OT-II breeders, respectively. We thank Maria Protti (San Raffaele Scientific Institute, Milan, Italy) for critically revising the manuscript. Amgen Inc. (Thousand Oaks, CA, USA) kindly provided us with anti-IL17RA and anti-IL-17 antibodies. We thank Caligaris-Cappio (San Raffaele Scientific Institute, Milan, Italy) for his intellectual contribuition to the project. The work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), AIRC 5 × 1000 Molecular Clinical Oncology Special Program, Milan, IT (grant no. 9965 to M.B. and G.T.). This work was also supported by research grants from the National Cancer Institute: CA190045 (M.C.), CA186781 (M.C.) CA168762 (V.S.R.), CA186781 (P.L.B.), and CA195688 (P.L.B.). A.C. was awarded a fellowship from AIRC/FIRC and A.C. and A.B. conducted this study in partial fulfillment of their Ph.D. at San Raffaele University.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
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.
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.
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U2 - 10.1038/s41467-018-07305-8
DO - 10.1038/s41467-018-07305-8
M3 - Article
C2 - 30510245
AN - SCOPUS:85057599323
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4832
ER -