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 Huynh, Antonio Sacco, Yu-Tzu Tai, Marta Chesi, P. Leif Bergsagel, Aldo M. Roccaro, Jamil Azzi, Irene M. Ghobrial
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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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 3

Treg depletion in DEREG mice leads to extended survival of Vk*MYC-injected mice, while adoptive transfer of Tregs promotes tumor progression in vivo.

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Treg depletion in DEREG mice leads to extended survival of Vk*MYC-inject...
(A) Diphtheria toxin (DT) or PBS was injected 3 times (day 5, day 12, and day 19) after Vk*MYC injection into DEREG mice or wild-type mice (n = 7/group). (B) Proportion of Vk*MYC cells (CD138+B220– cells) in the BM of each group at day 20 after Vk*MYC injection. Three mice from each group were sacrificed at day 20 for analysis of BM Vk*MYC frequency. Significant tumor reduction occurred in the DEREG mice treated with DT compared with control mice. P values determined by 2-tailed t test with Bonferroni’s correction. (C) Kaplan-Meier curve showing significant increase in survival of DEREG mice treated with DT (DEREG + DT) compared with control groups (DEREG + PBS, wild type + DT) (n = 7/group). P < 0.0001 by log-rank test. (D) For Treg transfer experiments, 3 × 106 non-Tregs were injected with or without 1 × 106 Tregs i.v. into Rag2-KO mice followed by Vk*MYC cell injection 5 days afterwards. (E) Kaplan-Meier curve showing mice injected with Tregs and CD3+ non-Tregs (Tregs + CD3+ non-Tregs: median survival 21 days) had significantly shorter survival compared with mice injected only with CD3+ non-Tregs (CD3+ non-Tregs: median survival 25.5 days) (n = 6/group). P < 0.01 by log-rank test. (F) FACS analysis of mice BM showing significant increase of BM Tregs in the Tregs + CD3+ non-Tregs group compared with CD3+ non-Tregs group (n = 3/group). P value determined by 2-tailed t test. Error bars indicate SD.