Blocking IFNAR1 inhibits multiple myeloma–driven Treg expansion and immunosuppression
Yawara Kawano, … , Jamil Azzi, Irene M. Ghobrial
Yawara Kawano, … , Jamil Azzi, Irene M. Ghobrial
Published March 20, 2018
Citation Information: J Clin Invest. 2018;128(6):2487-2499. https://doi.org/10.1172/JCI88169.
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Research Article Hematology Immunology

Blocking IFNAR1 inhibits multiple myeloma–driven Treg expansion and immunosuppression

Abstract

Despite significant advances in the treatment of multiple myeloma (MM), most patients succumb to disease progression. One of the major immunosuppressive mechanisms that is believed to play a role in myeloma progression is the expansion of regulatory T cells (Tregs). In this study, we demonstrate that myeloma cells drive Treg expansion and activation by secreting type 1 interferon (IFN). Blocking IFN α and β receptor 1 (IFNAR1) on Tregs significantly decreases both myeloma-associated Treg immunosuppressive function and myeloma progression. Using syngeneic transplantable murine myeloma models and bone marrow (BM) aspirates of MM patients, we found that Tregs were expanded and activated in the BM microenvironment at early stages of myeloma development. Selective depletion of Tregs led to a complete remission and prolonged survival in mice injected with myeloma cells. Further analysis of the interaction between myeloma cells and Tregs using gene sequencing and enrichment analysis uncovered a feedback loop, wherein myeloma-cell-secreted type 1 IFN induced proliferation and expansion of Tregs. By using IFNAR1-blocking antibody treatment and IFNAR1-knockout Tregs, we demonstrated a significant decrease in myeloma-associated Treg proliferation, which was associated with longer survival of myeloma-injected mice. Our results thus suggest that blocking type 1 IFN signaling represents a potential strategy to target immunosuppressive Treg function in MM.

Authors

Yawara Kawano, Oksana Zavidij, Jihye Park, Michele Moschetta, Katsutoshi Kokubun, Tarek H. Mouhieddine, Salomon Manier, Yuji Mishima, Naoka Murakami, Mark Bustoros, Romanos Sklavenitis Pistofidis, Mairead Reidy, Yu J. Shen, Mahshid Rahmat, Pavlo Lukyanchykov, Esilida Sula Karreci, Shokichi Tsukamoto, Jiantao Shi, Satoshi Takagi, Daisy Huynh, Antonio Sacco, Yu-Tzu Tai, Marta Chesi, P. Leif Bergsagel, Aldo M. Roccaro, Jamil Azzi, Irene M. Ghobrial

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Figure 6

Type 1 IFN signaling associated with Treg activation and overall patient survival.

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Type 1 IFN signaling associated with Treg activation and overall patient...
(A) Vk*MYC BM Tregs show an enrichment for type 1 IFN–related mRNA signature compared with control BM Tregs, as presented by GSEA. The green curves show the enrichment score and reflect the degree to which each gene (black vertical lines) is represented at the top or bottom of the ranked gene list. The heatmap indicates the relative abundance (red to blue) of the genes specifically enriched in the Vk*MYC Tregs as compared with control Tregs. FDR and P values and are shown for each gene set analyzed. (B) IFN-β secretion from Vk*MYC cells. IFN-β secretion, detected by ELISA, in Vk*MYC cell culture supernatants was significantly higher compared with the supernatants of control B cells obtained from C57BL/6 mice. Average of experiments performed in triplicate is shown. The experiment was repeated 3 times. (C) Myeloma cells from MM patients show enrichment in type 1 IFN signaling pathway compared with cells from healthy donors. (D) Differential gene expression levels for genes involved in type 1 IFN production. (E) IFNA1 overexpression is associated with worse overall survival in MM patients. (F) Expression of TLR8 significantly correlates with worse outcome in MM patients. *P < 0.05; **P < 0.01 by 2-tailed t test. Error bars indicate SD.