Blocking IFNAR1 inhibits multiple myeloma-driven Treg expansion and immunosuppression

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 HuynhAntonio Sacco, Yu Tzu Tai, Marta Chesi, Peter Leif Bergsagel, Aldo M. Roccaro, Jamil Azzi, Irene M. Ghobrial

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13 Scopus citations

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 a and ß 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.

Original languageEnglish (US)
Pages (from-to)2487-2499
Number of pages13
JournalJournal of Clinical Investigation
Volume128
Issue number6
DOIs
StatePublished - Jun 1 2018

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ASJC Scopus subject areas

  • Medicine(all)

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Kawano, Y., Zavidij, O., Park, J., Moschetta, M., Kokubun, K., Mouhieddine, T. H., Manier, S., Mishima, Y., Murakami, N., Bustoros, M., Pistofidis, R. S., Reidy, M., Shen, Y. J., Rahmat, M., Lukyanchykov, P., Karreci, E. S., Tsukamoto, S., Shi, J., Takagi, S., ... Ghobrial, I. M. (2018). Blocking IFNAR1 inhibits multiple myeloma-driven Treg expansion and immunosuppression. Journal of Clinical Investigation, 128(6), 2487-2499. https://doi.org/10.1172/JCI88169