Blocking IFNRA1 inhibits Multiple Myeloma-driven regulatory T-cell expansion and immunosuppression

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 IFNAR1 (interferon alpha and beta receptor 1) on Tregs significantly decreases both, myeloma-associated Treg immunosupporessive function and myeloma progression. Using syngeneic transplantable murine myeloma models and bone marrow (BM) aspirates of multiple myeloma 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 Trage function in MM. Overall design: RNA sequencing of 3 BM of Vk*MYC-injected and 3 BM of control mice尽管多发性骨髓瘤（multiple myeloma, MM）的治疗已取得显著进展，但多数患者最终仍会因疾病进展死亡。目前认为，在骨髓瘤进展过程中发挥作用的主要免疫抑制机制之一，是调节性T细胞（regulatory T-cells, Tregs）的扩增。本研究证实，骨髓瘤细胞可通过分泌I型干扰素（type-1 interferon, IFN）介导调节性T细胞的扩增与活化。阻断调节性T细胞表面的干扰素α/β受体1（interferon alpha and beta receptor 1, IFNAR1），可显著降低骨髓瘤相关调节性T细胞的免疫抑制功能，并延缓骨髓瘤进展。本研究采用同基因可移植小鼠骨髓瘤模型与多发性骨髓瘤患者的骨髓（bone marrow, BM）抽吸标本，发现骨髓瘤发生早期，骨髓微环境中即可出现调节性T细胞的扩增与活化。选择性清除调节性T细胞，可使接种骨髓瘤细胞的小鼠达到完全缓解并延长生存期。通过基因测序与富集分析进一步解析骨髓瘤细胞与调节性T细胞的相互作用，本研究发现一条反馈环路：骨髓瘤细胞分泌的I型干扰素可诱导调节性T细胞增殖扩增。通过采用IFNAR1阻断抗体处理及构建IFNAR1敲除的调节性T细胞，本研究证实骨髓瘤相关调节性T细胞的增殖可被显著抑制，该效应与接种骨髓瘤细胞的小鼠生存期延长密切相关。综上，本研究结果提示，阻断I型干扰素信号通路或可成为靶向多发性骨髓瘤中免疫抑制性调节性T细胞功能的潜在治疗策略。实验整体设计：对3只Vk*MYC注射小鼠及3只对照小鼠的骨髓组织进行RNA测序。