Depletion of exhausted alloreactive T cells enables targeting of stem-like memory T cells to generate tumor-specific immunity.

Some hematological malignancies such as multiple myeloma are inherently resistant to immune-mediated antitumor responses, the cause of which remains unknown. Allogeneic bone marrow transplantation (alloBMT) is the only curative immunotherapy for hematological malignancies due to profound graft-versus-tumor (GVT) effects, but relapse remains the major cause of death. We developed murine models of alloBMT where the hematological malignancy is either sensitive [acute myeloid leukemia (AML)] or resistant (myeloma) to GVT effects. We found that CD8+ T cell exhaustion in bone marrow was primarily alloantigen-driven, with expression of inhibitory ligands present on myeloma but not AML. Because of this tumor-independent exhaustion signature, immune checkpoint inhibition (ICI) in myeloma exacerbated graft-versus-host disease (GVHD) without promoting GVT effects. Administration of post-transplant cyclophosphamide (PT-Cy) depleted donor T cells with an exhausted phenotype and spared T cells displaying a stem-like memory phenotype with chromatin accessibility present in cytokine signaling genes, including the interleukin-18 (IL-18) receptor. Whereas ICI with anti-PD-1 or anti-TIM-3 remained ineffective after PT-Cy, administration of a decoy-resistant IL-18 (DR-18) strongly enhanced GVT effects in both myeloma and leukemia models, without exacerbation of GVHD. We thus defined mechanisms of resistance to T cell-mediated antitumor effects after alloBMT and described an immunotherapy approach targeting stem-like memory T cells to enhance antitumor immunity.

Correction: Inhibition of thioredoxin 1 leads to apoptosis in drug-resistant multiple myeloma.

[This corrects the article DOI: 10.18632/oncotarget.3795.].

Treg and Oligoclonal Expansion of Terminal Effector CD8+ T Cell as Key Players in Multiple Myeloma.

The classical paradigm of host-tumor interaction, i.e. elimination, equilibrium, and escape (EEE), is reflected in the clinical behavior of myeloma which progresses from the premalignant condition, Monoclonal Gammopathy of Unknown Significance (MGUS). Despite the role of other immune cells, CD4+ regulatory T cells (Treg) and cytotoxic CD8+ T cells have emerged as the dominant effectors of host control of the myeloma clone. Progression from MGUS to myeloma is associated with alterations in Tregs and terminal effector CD8+ T cells (TTE). These changes involve CD39 and CD69 expression, affecting the adenosine pathway and residency in the bone marrow (BM) microenvironment, together with oligoclonal expansion within CD8+ TTE cells. In this mini-review article, in the context of earlier data, we summarize our recent understanding of Treg involvement in the adenosine pathway, the significance of oligoclonal expansion within CD8+ TTE cells and BM-residency of CD8+ TTE cells in MGUS and newly diagnosed multiple myeloma patients.

Inverse relationship between oligoclonal expanded CD69- TTE and CD69+ TTE cells in bone marrow of multiple myeloma patients.

CD8+CD57+ terminal effector T (TTE) cells are a component of marrow-infiltrating lymphocytes and may contribute to the altered immune responses in multiple myeloma (MM) patients. We analyzed TTE cells in the bone marrow (BM) and peripheral blood (PB) of age-matched controls and patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and newly diagnosed (ND) MM using flow cytometry, mass cytometry, and FlowSOM clustering. TTE cells are heterogeneous in all subjects, with BM containing both CD69- and CD69+ subsets, while only CD69- cells are found in PB. Within the BM-TTE compartment, CD69- and CD69+ cells are found in comparable proportions in controls, while CD69- cells are dominant in MGUS and SMM and predominantly either CD69- or CD69+ cells in NDMM. A positive relationship between CD69+TTE and CD69-TTE cells is observed in the BM of controls, lost in MGUS, and converted to an inverse relationship in NDMM. CD69-TTE cells include multiple oligoclonal expansions of T-cell receptor/Vß families shared between BM and PB of NDMM. Oligoclonal expanded CD69-TTE cells from the PB include myeloma-reactive cells capable of killing autologous CD38hi plasma cells in vitro, involving degranulation and high expression of perforin and granzyme. In contrast to CD69-TTE cells, oligoclonal expansions are not evident within CD69+TTE cells, which possess low perforin and granzyme expression and high inhibitory checkpoint expression and resemble T resident memory cells. Both CD69-TTE and CD69+TTE cells from the BM of NDMM produce large amounts of the inflammatory cytokines interferon-γ and tumor necrosis factor α. The balance between CD69- and CD69+ cells within the BM-TTE compartment may regulate immune responses in NDMM and contribute to the clinical heterogeneity of the disease.

ASC Modulates CTL Cytotoxicity and Transplant Outcome Independent of the Inflammasome.

The adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) is known to facilitate caspase-1 activation, which is essential for innate host immunity via the formation of the inflammasome complex, a multiprotein structure responsible for processing IL1ß and IL18 into their active moieties. Here, we demonstrated that ASC-deficient CD8+ T cells failed to induce severe graft-versus-host disease (GVHD) and had impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects were inflammasome independent because GVHD lethality was not altered in recipients of caspase-1/11-deficient T cells. We also demonstrated that ASC deficiency resulted in a decrease in cytolytic function, with a reduction in granzyme B secretion and CD107a expression by CD8+ T cells. Altogether, our findings highlight that ASC represents an attractive therapeutic target for improving outcomes of clinical transplantation.

IL-6 dysregulation originates in dendritic cells and mediates graft-versus-host disease via classical signaling.

Graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloSCT) is characterized by interleukin-6 (IL-6) dysregulation. IL-6 can mediate effects via various pathways, including classical, trans, and cluster signaling. Given the recent availability of agents that differentially inhibit these discrete signaling cascades, understanding the source and signaling and cellular targets of this cytokine is paramount to inform the design of clinical studies. Here we demonstrate that IL-6 secretion from recipient dendritic cells (DCs) initiates the systemic dysregulation of this cytokine. Inhibition of DC-driven classical signaling after targeted IL-6 receptor (IL-6R) deletion in T cells eliminated pathogenic donor Th17/Th22 cell differentiation and resulted in long-term survival. After engraftment, donor DCs assume the same role, maintaining classical IL-6 signaling-dependent GVHD responses. Surprisingly, cluster signaling was not active after transplantation, whereas inhibition of trans signaling with soluble gp130Fc promoted severe, chronic cutaneous GVHD. The latter was a result of exaggerated polyfunctional Th22-cell expansion that was reversed by IL-22 deletion or IL-6R inhibition. Importantly, inhibition of IL-6 classical signaling did not impair the graft-versus-leukemia effect. Together, these data highlight IL-6 classical signaling and downstream Th17/Th22 differentiation as important therapeutic targets after alloSCT.

Mass Cytometry Discovers Two Discrete Subsets of CD39-Treg Which Discriminate MGUS From Multiple Myeloma.

Multiple Myeloma (MM) is preceded by the clinically stable condition monoclonal gammopathy of undetermined significance (MGUS). Critical immune events that discriminate MGUS from newly diagnosed MM (ND)MM patients remain unknown, but may involve changes in the regulatory T cell (Treg) compartment that favor myeloma growth. To address this possibility, we used mass cytometry and the unsupervised clustering algorithm Flow self-organizing map (FlowSOM) to interrogate the distribution of multiple subsets within CD25+CD127low/negTreg in matched bone marrow (BM) and peripheral blood (PB) of MGUS and NDMM patients. Both mass cytometry and flow cytometry confirmed a trend toward prevalence of CD39-Treg within the Treg compartment in BM and PB of NDMM patients compared to CD39-Treg in MGUS patients. FlowSOM clustering displayed a phenotypic organization of Treg into 25 metaclusters that confirmed Treg heterogeneity. It identified two subsets which emerged within CD39-Treg of NDMM patients that were negligible or absent in CD39-Treg of MGUS patients. One subset was found in both BM and PB which phenotypically resembled activated Treg based on CD45RO, CD49d, and CD62L expression; another subset resembled BM-resident Treg based on its tissue-resident CD69+CD62L-CD49d- phenotype and restricted location within the BM. Both subsets co-expressed PD-1 and TIGIT, but PD-1 was expressed at higher levels on BM-resident Treg than on activated Treg. Within BM, both subsets had limited Perforin and Granzyme B production, whilst activated Treg in PB acquired high Perforin and Granzyme B production. In conclusion, the use of mass cytometry and FlowSOM clustering discovered two discrete subsets of CD39-Treg which are discordant in MGUS and NDMM patients and may be permissive of myeloma growth which warrants further study. Understanding the regulatory properties of these subsets may also advance MGUS and MM diagnosis, prognosis, and therapeutic implications for MM patients.

Chemotherapy followed by anti-CD137 mAb immunotherapy improves disease control in a mouse myeloma model.

Immunotherapy holds promise for multiple myeloma (MM) patients but little is known about how MM-induced immunosuppression influences response to therapy. Here, we investigated the impact of disease progression on immunotherapy efficacy in the Vk*MYC mouse model. Treatment with agonistic anti-CD137 (4-1BB) mAbs efficiently protected mice when administered early but failed to contain MM growth when delayed more than three weeks after Vk*MYC tumor cell challenge. The quality of CD8+ T cell response to CD137 stimulation was not altered by the presence of MM, but CD8+ T cell numbers were profoundly reduced at the time of treatment. Our data suggest that an insufficient ratio of CD8+ T cells over MM cells (CD8/MM) accounts for the loss of anti-CD137 mAb efficacy. We established serum M-protein levels prior to therapy as a predictive factor of response. Moreover, we developed an in silico model to capture the dynamic interactions between CD8+ T cells and MM cells. Finally, we explored two methods to improve the CD8/MM ratio: anti-CD137 mAb immunotherapy combined with Treg-depletion or administered after chemotherapy treatment with cyclophosphamide or melphalan efficiently reduced MM burden and prolonged survival. Altogether, our data indicate that consolidation treatment with anti-CD137 mAbs might prevent MM relapse.

Bone marrow transplantation generates T cell-dependent control of myeloma in mice.

Transplantation with autologous hematopoietic progenitors remains an important consolidation treatment for patients with multiple myeloma (MM) and is thought to prolong the disease plateau phase by providing intensive cytoreduction. However, transplantation induces inflammation in the context of profound lymphodepletion that may cause hitherto unexpected immunological effects. We developed preclinical models of bone marrow transplantation (BMT) for MM using Vk*MYC myeloma-bearing recipient mice and donor mice that were myeloma naive or myeloma experienced to simulate autologous transplantation. Surprisingly, we demonstrated broad induction of T cell-dependent myeloma control, most efficiently from memory T cells within myeloma-experienced grafts, but also through priming of naive T cells after BMT. CD8+ T cells from mice with controlled myeloma had a distinct T cell receptor (TCR) repertoire and higher clonotype overlap relative to myeloma-free BMT recipients. Furthermore, T cell-dependent myeloma control could be adoptively transferred to secondary recipients and was myeloma cell clone specific. Interestingly, donor-derived IL-17A acted directly on myeloma cells expressing the IL-17 receptor to induce a transcriptional landscape that promoted tumor growth and immune escape. Conversely, donor IFN-γ secretion and signaling were critical to protective immunity and were profoundly augmented by CD137 agonists. These data provide new insights into the mechanisms of action of transplantation in myeloma and provide rational approaches to improving clinical outcomes.

Myeloma escape after stem cell transplantation is a consequence of T-cell exhaustion and is prevented by TIGIT blockade.

Autologous stem cell transplantation (SCT) remains a standard of care for multiple myeloma (MM) patients and prolongs progression-free survival. A small cohort of patients achieve long-term control of disease, but the majority of patients ultimately relapse, and the mechanisms permitting disease progression remain unclear. In this study, we used a preclinical model of autologous SCT for myeloma where the disease either progressed (MM relapsed) or was controlled. In the bone marrow (BM), inhibitory receptor expression on CD8+ T cells correlated strongly with myeloma progression after transplant. In conjunction, the costimulatory/adhesion receptor CD226 (DNAM-1) was markedly downregulated. Interestingly, DNAM-1- CD8+ T cells in MM-relapsed mice had an exhausted phenotype, characterized by upregulation of multiple inhibitory receptors, including T-cell immunoglobulin and ITIM domains (TIGIT) and programmed cell death protein 1 (PD-1) with decreased T-bet and increased eomesodermin expression. Immune checkpoint blockade using monoclonal antibodies against PD-1 or TIGIT significantly prolonged myeloma control after SCT. Furthermore, CD8+ T cells from MM-relapsed mice exhibited high interleukin-10 (IL-10) secretion that was associated with increased TIGIT and PD-1 expression. However, while donor-derived IL-10 inhibited myeloma control post-SCT, this was independent of IL-10 secretion by or signaling to T cells. Instead, the donor myeloid compartment, including colony-stimulating factor 1 receptor-dependent macrophages and an IL-10-secreting dendritic cell population in the BM, promoted myeloma progression. Our findings highlight PD-1 or TIGIT blockade in conjunction with SCT as a potent combination therapy in the treatment of myeloma.

Granulocytes Are Unresponsive to IL-6 Due to an Absence of gp130.

IL-6 mediates broad physiological and pathological effects through its receptor signal transducing unit gp130. Due to the reportedly wide cellular expression of gp130, IL-6 is thought to signal ubiquitously via gp130 complex formation with membrane-bound IL-6Rα or soluble IL-6Rα. gp130 signaling primarily induces p-STAT3 and p-STAT1. In contrast to the previous dogma, we show in this article that circulating mouse and human granulocytes are unable to induce p-STAT3 or p-STAT1 after stimulation with IL-6 or an IL-6/soluble IL-6R complex. Furthermore, we demonstrate that this is due to a lack of gp130 expression on mouse and human granulocytes, despite their expression of membrane-bound IL-6R. Importantly, the absence of gp130 is not only a feature of mature granulocytes in healthy individuals, it is also observed after allogeneic stem cell transplantation. Moreover, granulocyte gp130 expression is lost during maturation, because granulocyte-monocyte progenitor cells express gp130 and respond to IL-6. Given that granulocytes constitute 50-70% of circulating leukocytes, this indicates a significantly smaller scope of IL-6 signaling than previously anticipated and has important implications for therapeutic IL-6 inhibition and the mechanisms of action thereof.

Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment.

Tumor-promoting inflammation and avoiding immune destruction are hallmarks of cancer. Here, we demonstrate that the pro-inflammatory cytokine interleukin (IL)-18 is critically involved in these hallmarks in multiple myeloma (MM). Mice deficient for IL-18 were remarkably protected from Vk∗MYC MM progression in a CD8+ T cell-dependent manner. The MM-niche-derived IL-18 drove generation of myeloid-derived suppressor cells (MDSCs), leading to accelerated disease progression. A global transcriptome analysis of the immune microenvironment in 73 MM patients strongly supported the negative impact of IL-18-driven MDSCs on T cell responses. Strikingly, high levels of bone marrow plasma IL-18 were associated with poor overall survival in MM patients. Furthermore, our preclinical studies suggested that IL-18 could be a potential therapeutic target in MM.

Oncogenic JAK2V617F causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms.

Recent evidence has revealed that oncogenic mutations may confer immune escape. A better understanding of how an oncogenic mutation affects immunosuppressive programmed death ligand 1 (PD-L1) expression may help in developing new therapeutic strategies. We show that oncogenic JAK2 (Janus kinase 2) activity caused STAT3 (signal transducer and activator of transcription 3) and STAT5 phosphorylation, which enhanced PD-L1 promoter activity and PD-L1 protein expression in JAK2V617F-mutant cells, whereas blockade of JAK2 reduced PD-L1 expression in myeloid JAK2V617F-mutant cells. PD-L1 expression was higher on primary cells isolated from patients with JAK2V617F-myeloproliferative neoplasms (MPNs) compared to healthy individuals and declined upon JAK2 inhibition. JAK2V617F mutational burden, pSTAT3, and PD-L1 expression were highest in primary MPN patient-derived monocytes, megakaryocytes, and platelets. PD-1 (programmed death receptor 1) inhibition prolonged survival in human MPN xenograft and primary murine MPN models. This effect was dependent on T cells. Mechanistically, PD-L1 surface expression in JAK2V617F-mutant cells affected metabolism and cell cycle progression of T cells. In summary, we report that in MPN, constitutive JAK2/STAT3/STAT5 activation, mainly in monocytes, megakaryocytes, and platelets, caused PD-L1-mediated immune escape by reducing T cell activation, metabolic activity, and cell cycle progression. The susceptibility of JAK2V617F-mutant MPN to PD-1 targeting paves the way for immunomodulatory approaches relying on PD-1 inhibition.

Eomesodermin promotes the development of type 1 regulatory T (TR1) cells.

Type 1 regulatory T (TR1) cells are Foxp3- interleukin-10 (IL-10)-producing CD4+ T cells with potent immunosuppressive properties, but their requirements for lineage development have remained elusive. We show that TR1 cells constitute the most abundant regulatory population after allogeneic bone marrow transplantation (BMT), express the transcription factor Eomesodermin (Eomes), and are critical for the prevention of graft-versus-host disease. We demonstrate that Eomes is required for TR1 cell differentiation, during which it acts in concert with the transcription factor B lymphocyte-induced maturation protein-1 (Blimp-1) by transcriptionally activating IL-10 expression and repressing differentiation into other T helper cell lineages. We further show that Eomes induction in TR1 cells requires T-bet and donor macrophage-derived IL-27. Thus, we define the cellular and transcriptional control of TR1 cell differentiation during BMT, opening new avenues to therapeutic manipulation.

The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells.

We have discovered that a small cationic molecule, GW4869, is cytotoxic to a subset of myeloma cell lines and primary myeloma plasma cells. Biochemical analysis revealed that GW4869 binds to anionic phospholipids such as phosphatidylserine - a lipid normally confined to the intracellular side of the cell membrane. However, interestingly, phosphatidylserine was expressed on the surface of all myeloma cell lines tested (n = 12) and 9/15 primary myeloma samples. Notably, the level of phosphatidylserine expression correlated well with sensitivity to GW4869. Inhibition of cell surface phosphatidylserine exposure with brefeldin A resulted in resistance to GW4869. Finally, GW4869 was shown to delay the growth of phosphatidylserine-high myeloma cells in vivo. To the best of our knowledge, this is the first example of using a small molecule to target phosphatidylserine on malignant cells. This study may provide the rationale for the development of phosphatidylserine-targeting small molecules for the treatment of surface phosphatidylserine-expressing cancers.

Targeted knockdown of DJ-1 induces multiple myeloma cell death via KLF6 upregulation.

Multiple myeloma (MM) is an incurable plasma B cell malignancy. Despite recent advancements in anti-MM therapies, development of drug resistance remains a major clinical hurdle. DJ-1, a Parkinson's disease-associated protein, is upregulated in many cancers and its knockdown suppresses tumor growth and overcomes chemoresistance. However, the role of DJ-1 in MM remains unknown. Using gene expression databases we found increased DJ-1 expression in MM patient cells, which correlated with shorter overall survival and poor prognosis in MM patients. Targeted DJ-1 knockdown using siRNAs induced necroptosis in myeloma cells. We found that Krüppel-like factor 6 (KLF6) is expressed at lower levels in myeloma cells compared to PBMCs, and DJ-1 knockdown increased KLF6 expression in myeloma cells. Targeted knockdown of KLF6 expression in DJ-1 knockdown myeloma cells rescued these cells from undergoing cell death. Higher DJ-1 levels were observed in bortezomib-resistant myeloma cells compared to parent cells, and siRNA-mediated DJ-1 knockdown reversed bortezomib resistance. DJ-1 knockdown increased KLF6 expression in bortezomib-resistant myeloma cells, and subsequent siRNA-mediated KLF6 knockdown rescued bortezomib-resistant myeloma cells from undergoing cell death. We also demonstrated that specific siRNA-mediated DJ-1 knockdown reduced myeloma cell growth under a hypoxic microenvironment. DJ-1 knockdown reduced the expression of HIF-1α and its target genes in hypoxic-myeloma cells, and overcame hypoxia-induced bortezomib resistance. Our findings demonstrate that elevated DJ-1 levels correlate with myeloma cell survival and acquisition of bortezomib resistance. Thus, we propose that inhibiting DJ-1 may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM patients.

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-Ðºß inhibition.

Multiple myeloma (MM) is a B-cell malignancy characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Introduction of the proteasome-inhibitor bortezomib has improved MM prognosis and survival; however hypoxia-induced or acquired bortezomib resistance remains a clinical problem. This study highlighted the role of thioredoxin reductase 1 (TrxR1) in the hypoxia-induced and acquired bortezomib resistance in MM. Higher TrxR1 gene expression correlated with high-risk disease, adverse overall survival, and poor prognosis in myeloma patients. We demonstrated that hypoxia induced bortezomib resistance in myeloma cells and increased TrxR1 protein levels. Inhibition of TrxR1 using auranofin overcame hypoxia-induced bortezomib resistance and restored the sensitivity of hypoxic-myeloma cells to bortezomib. Hypoxia increased NF-Ðºß subunit p65 nuclear protein levels and TrxR1 inhibition decreased hypoxia-induced NF-Ðºß p65 protein levels in the nucleus and reduced the expression of NF-кß-regulated genes. In addition, higher TrxR1 protein levels were observed in bortezomib-resistant myeloma cells compared to the naïve cells, and its inhibition using either auranofin or TrxR1-specific siRNAs reversed bortezomib resistance. TrxR1 inhibition reduced p65 mRNA and protein expression in bortezomib-resistant myeloma cells, and also decreased the expression of NF-кß-regulated anti-apoptotic and proliferative genes. Thus, TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance by inhibiting the NF-Ðºß signaling pathway. Our findings demonstrate that elevated TrxR1 levels correlate with the acquisition of bortezomib resistance in MM. We propose considering TrxR1-inhibiting drugs, such as auranofin, either for single agent or combination therapy to circumvent bortezomib-resistance and improve survival outcomes of MM patients.

Cross-talk between two antioxidants, thioredoxin reductase and heme oxygenase-1, and therapeutic implications for multiple myeloma.

Multiple myeloma (MM) is characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Despite recent advancements in anti-myeloma therapies, MM remains an incurable disease. Antioxidant molecules are upregulated in many cancers, correlating with tumor proliferation, survival, and chemoresistance and therefore, have been suggested as potential therapeutic targets. This study investigated the cross-talk between two antioxidant molecules, thioredoxin reductase (TrxR) and heme oxygenase-1 (HO-1), and their therapeutic implications in MM. We found that although auranofin, a TrxR inhibitor, significantly inhibited TrxR activity by more than 50% at lower concentrations, myeloma cell proliferation was only inhibited at higher concentrations of auranofin. Inhibition of TrxR using lower auranofin concentrations induced HO-1 protein expression in myeloma cells. Using a sub-lethal concentration of auranofin to inhibit TrxR activity in conjunction with HO-1 inhibition significantly decreased myeloma cell growth and induced apoptosis. TrxR was shown to regulate HO-1 via the Nrf2 signaling pathway in a ROS-dependent manner. Increased HO-1 mRNA levels were observed in bortezomib-resistant myeloma cells compared to parent cells and HO-1 inhibition restored the sensitivity to bortezomib in bortezomib-resistant myeloma cells. These findings indicate that concurrent inhibition of HO-1 with either a TrxR inhibitor or with bortezomib would improve therapeutic outcomes in MM patients. Hence, our findings further support the need to target multiple antioxidant systems alone or in combination with other therapeutics to improve therapeutic outcomes in MM patients.

Immune responses in multiple myeloma: role of the natural immune surveillance and potential of immunotherapies.

Multiple myeloma (MM) is a tumor of terminally differentiated B cells that arises in the bone marrow. Immune interactions appear as key determinants of MM progression. While myeloid cells foster myeloma-promoting inflammation, Natural Killer cells and T lymphocytes mediate protective anti-myeloma responses. The profound immune deregulation occurring in MM patients may be involved in the transition from a premalignant to a malignant stage of the disease. In the last decades, the advent of stem cell transplantation and new therapeutic agents including proteasome inhibitors and immunoregulatory drugs has dramatically improved patient outcomes, suggesting potentially key roles for innate and adaptive immunity in disease control. Nevertheless, MM remains largely incurable for the vast majority of patients. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential of very long term disease control. Here, we review the immunological microenvironment in myeloma. We discuss the role of naturally arising anti-myeloma immune responses and their potential corruption in MM patients. Finally, we detail the numerous promising immune-targeting strategies approved or in clinical trials for the treatment of MM.

Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease.

The primacy of the gastrointestinal (GI) tract in dictating the outcome of graft-versus-host disease (GVHD) is broadly accepted; however, the mechanisms controlling this effect are poorly understood. Here, we demonstrate that GVHD markedly enhances alloantigen presentation within the mesenteric lymph nodes (mLNs), mediated by donor CD103(+)CD11b(-) dendritic cells (DCs) that migrate from the colon under the influence of CCR7. Expansion and differentiation of donor T cells specifically within the mLNs is driven by profound levels of alloantigen, IL-12, and IL-6 promoted by Toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signals. Critically, alloantigen presentation in the mLNs imprints gut-homing integrin signatures on donor T cells, leading to their emigration into the GI tract where they mediate fulminant disease. These data identify a critical, anatomically distinct, donor DC subset that amplifies GVHD. We thus highlight multiple therapeutic targets and the ability of GVHD, once initiated by recipient antigen-presenting cells, to generate a profound, localized, and lethal feed-forward cascade of donor DC-mediated indirect alloantigen presentation and cytokine secretion within the GI tract.