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.

We retrospectively reviewed 104 biopsy specimens of previously untreated skin acute graft-versus-host disease (GVHD) within 100 days after allogeneic stem cell transplantation, and analyzed the relationship between types of infiltrating cells and clinical outcomes. Counting the total number of CD8 ؉ T cells, CD163 ؉ macrophages, and CD1a ؉ dendritic cells in 4 fields under original magnification IntroductionMacrophages are phagocytic cells with various abilities, such as phagocytosis, antigen-presenting, and secretion of cytokines. 1,2 Recently, it was revealed in human sequential biopsy data that recipient macrophages contributed to acute graft-versus-host disease (GVHD) by antigen-presenting and secreting cytokines, causing the activation and proliferation of CD8 ϩ T cells. 3 We focused on macrophage involvement in acute GVHD, especially on the relationship between the macrophage infiltration of skin lesions and refractory GVHD. MethodsBetween January 1997 and October 2007 at the Japanese Red Cross Nagoya First Hospital, we used skin biopsy specimens within 100 days after allogeneic stem cell transplantation (allo-SCT) of skin lesions clinically considered acute GVHD without any GVHD treatment from 104 patients who underwent allo-SCTs. We analyzed the relationship between types of infiltrating cells and clinical outcomes by counting the total number of CD8 ϩ T cells, CD163 ϩ macrophages, and CD1a ϩ dendritic cells in 4 fields of a skin biopsy specimen under original magnification ϫ200. Immunohistochemical analysis using paraffin sections was performed using monoclonal antibodies against CD8, CD163, and CD1a (Novocastra). CD163 is a member of the scavenger receptor cystein-rich superfamily and is an exclusive marker for macrophages, playing a major role in the scavenging components of damaged cells. [4][5][6][7] The endpoints of this study were the outcomes of acute GVHD and overall survival (OS). Acute GVHD was diagnosed and graded according to the consensus criteria. 8 We defined refractory GVHD as that exhibited by patients who had persistent lesions after primary steroid treatments. To establish parameters, we analyzed the numbers of infiltrating , disease risk (low vs high), human leukocyte antigen (HLA) disparity (match vs mismatch), donor source (related vs unrelated), graft source (bone marrow vs peripheral blood), age at allo-SCT (Յ 50 years vs Ͼ 50 years), conditioning regimen (conventional regimens vs reduced intensity regimens), and skin GVHD stage at biopsy (stages 1-2 vs stages 3-4). A significance level of P Ͻ .05 was used for all analyses, which were based on all data available as of August 31, 2008. Protocols were approved by the Japanese Red Cross Nagoya First Hospital's Institutional Review Board, and all patients provided informed consent in accordance with the Declaration of Helsinki. Table 1 summarizes the characteristics of patients and information gathered about GVHD. We divided patients into 4 groups according to the amount of infiltrating cells (FM and FT, 60.6%; MT and FM, 18.2%; MT...

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Tumor cell-platelet interactions contribute to tumor progression and metastasis in solid tumors. However, the role of platelets in hematological malignancies is not clear. We investigated the association of platelet activation status with clinical stages in multiple myeloma (MM) patients and explored the role of platelets in MM progression. Platelets were obtained from healthy donors and MM patients. We examined platelet activation status in MM patients by flow cytometry and transmission electron microscopy. We also observed the enriched pathways that are involved with platelet activation in RNA sequencing of platelets. MM cell lines were used to assess the effect of platelets on MM cell proliferation and their engraftment RNA sequencing of MM cell lines was performed to explore molecular mechanisms underlying MM cell-platelet interaction and a CRISPR/Cas9 knockout approach was used for validation. Platelets from MM patients were highly activated with disease progression. RNA sequencing of platelets revealed that genes involved in platelets were enriched in patients with smoldering MM (SMM) or MM. Platelets promoted MM cell proliferation and contributed to tumor engraftment in bone marrow RNA sequencing revealed that was upregulated in MM cell lines co-cultured with platelets, whereas knockout in MM cell lines abrogated the effects of platelets on MM cell proliferation and engraftment Platelets from MM patients were highly activated with disease progression. IL-1β is critical to platelet-mediated MM progression and might be a potential target for MM treatment..