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Pro-survival metabolic adaptations to stress in tumorigenesis remain less well defined. We find that multiple myeloma (MM) is unexpectedly dependent on beta-oxidation of long-chain fatty acids (FAs) for survival under both basal and stress conditions. However, under stress conditions, a second pro-survival signal is required to sustain FA oxidation (FAO). We previously found that CD28 is expressed on MM cells and transduces a significant pro-survival/chemotherapy resistance signal. We now find that CD28 signaling regulates autophagy/lipophagy that involves activation of the Ca2+âAMPKâULK1 axis and regulates the translation of ATG5 through HuR, resulting in sustained lipophagy, increased FAO, and enhanced MM survival. Conversely, blocking autophagy/lipophagy sensitizes MM to chemotherapy in vivo. Our findings link a pro-survival signal to FA availability needed to sustain the FAO required for cancer cell survival under stress conditions and identify lipophagy as a therapeutic target to overcome treatment resistance in MM.
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Autofagia , Supervivencia Celular , Mieloma Múltiple , Transducción de Señal , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Humanos , Autofagia/efectos de los fármacos , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Estrés Fisiológico/efectos de los fármacos , Ratones , Ácidos Grasos/metabolismo , Resistencia a Antineoplásicos , Proteína 5 Relacionada con la Autofagia/metabolismo , Proteína 5 Relacionada con la Autofagia/genéticaRESUMEN
Recent FDA approvals of chimeric antigen receptor (CAR) T cell therapy for multiple myeloma (MM) have reshaped the therapeutic landscape for this incurable cancer. In pivotal clinical trials B cell maturation antigen (BCMA) targeted, 4-1BB co-stimulated (BBζ) CAR T cells dramatically outperformed standard-of-care chemotherapy, yet most patients experienced MM relapse within two years of therapy, underscoring the need to improve CAR T cell efficacy in MM. We set out to determine if inhibition of MM bone marrow microenvironment (BME) survival signaling could increase sensitivity to CAR T cells. In contrast to expectations, blocking the CD28 MM survival signal with abatacept (CTLA4-Ig) accelerated disease relapse following CAR T therapy in preclinical models, potentially due to blocking CD28 signaling in CAR T cells. Knockout studies confirmed that endogenous CD28 expressed on BBζ CAR T cells drove in vivo anti-MM activity. Mechanistically, CD28 reprogrammed mitochondrial metabolism to maintain redox balance and CAR T cell proliferation in the MM BME. Transient CD28 inhibition with abatacept restrained rapid BBζ CAR T cell expansion and limited inflammatory cytokines in the MM BME without significantly affecting long-term survival of treated mice. Overall, data directly demonstrate a need for CD28 signaling for sustained in vivo function of CAR T cells and indicate that transient CD28 blockade could reduce cytokine release and associated toxicities.
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Metabolic flexibility has emerged as a critical determinant of CD8+ T-cell antitumor activity, yet the mechanisms driving the metabolic flexibility of T cells have not been determined. In this study, we investigated the influence of the nuclear cap-binding complex (CBC) adaptor protein ARS2 on mature T cells. In doing so, we discovered a novel signaling axis that endows activated CD8+ T cells with flexibility of glucose catabolism. ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events. Among these effects, the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2, a key determinant of CD8+ T-cell glucose utilization, interferon gamma production, and antitumor effector function. Importantly, PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation, revealing a novel means by which costimulation reprograms glucose metabolism in CD8+ T cells.
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Empalme Alternativo , Antígenos CD28 , Antígenos CD28/metabolismo , Empalme Alternativo/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Linfocitos T CD8-positivos , Glucosa/metabolismoRESUMEN
Macrophages represent the most abundant immune component of the tumor microenvironment and often exhibit protumorigenic (M2-like) phenotypes that contribute to disease progression. Despite their generally accepted protumorigenic role, macrophages can also display tumoricidal (or M1-like) behavior, revealing that macrophages can be functionally reprogrammed, depending on the cues received within the tumor microenvironment. Moreover, such plasticity may be achieved by pharmacologic or biologic interventions. To that end, we previously demonstrated that a novel immunomodulator termed the "very small size particle" (VSSP) facilitates maturation of dendritic cells and differentiation of myeloid-derived suppressor cells to APCs with reduced suppressive activity in cancer models. VSSP was further shown to act in the bone marrow to drive the differentiation of progenitors toward monocytes, macrophages, and dendritic cells during emergency myelopoiesis. However, the underlying mechanisms for VSSP-driven alterations in myeloid differentiation and function remained unclear. In this study, in mouse models, we focused on macrophages and tested the hypothesis that VSSP drives macrophages toward M1-like functional states via IRF8- and PU.1-dependent mechanisms. We further hypothesized that such VSSP-mediated actions would be accompanied by enhanced antitumor responses. Overall, we showed that (1) VSSP drives naive or M2-derived macrophages to M1-like states, (2) the M1-like state induced by VSSP occurs via IRF8- and PU.1-dependent mechanisms, and (3) single-agent VSSP induces an antitumor response that is accompanied by alterations in the intratumoral myeloid compartment. These results provide a deeper mechanistic underpinning of VSSP and strengthen its use to drive M1-like responses in host defense, including cancer.
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Nanopartículas , Neoplasias , Ratones , Animales , Gangliósidos , Macrófagos , Neoplasias/patología , Fenotipo , Factores Reguladores del Interferón , Microambiente TumoralRESUMEN
BACKGROUND: Immune suppression is common in neoplasia and a major driver is tumor-induced myeloid dysfunction. Yet, overcoming such myeloid cell defects remains an untapped strategy to reverse suppression and improve host defense. Exposure of bone marrow progenitors to heightened levels of myeloid growth factors in cancer or following certain systemic treatments promote abnormal myelopoiesis characterized by the production of myeloid-derived suppressor cells (MDSCs) and a deficiency in antigen-presenting cell function. We previously showed that a novel immune modulator, termed 'very small size particle' (VSSP), attenuates MDSC function in tumor-bearing mice, which was accompanied by an increase in dendritic cells (DCs) suggesting that VSSP exhibits myeloid differentiating properties. Therefore, here, we addressed two unresolved aspects of the mechanism of action of this unique immunomodulatory agent: (1) does VSSP alter myelopoiesis in the bone marrow to redirect MDSC differentiation toward a monocyte/macrophage or DC fate? and (2) does VSSP mitigate the frequency and suppressive function of human tumor-induced MDSCs? METHODS: To address the first question, we first used a murine model of granulocyte-colony stimulating factor-driven emergency myelopoiesis following chemotherapy-induced myeloablation, which skews myeloid output toward MDSCs, especially the polymorphonuclear (PMN)-MDSC subset. Following VSSP treatment, progenitors and their myeloid progeny were analyzed by immunophenotyping and MDSC function was evaluated by suppression assays. To strengthen rigor, we validated our findings in tumor-bearing mouse models. To address the second question, we conducted a clinical trial in patients with metastatic renal cell carcinoma, wherein 15 patients were treated with VSSP. Endpoints in this study included safety and impact on PMN-MDSC frequency and function. RESULTS: We demonstrated that VSSP diminished PMN-MDSCs by shunting granulocyte-monocyte progenitor differentiation toward monocytes/macrophages and DCs with heightened expression of the myeloid-dependent transcription factors interferon regulatory factor-8 and PU.1. This skewing was at the expense of expansion of granulocytic progenitors and rendered the remaining MDSCs less suppressive. Importantly, these effects were also demonstrated in a clinical setting wherein VSSP monotherapy significantly reduced circulating PMN-MDSCs, and their suppressive function. CONCLUSIONS: Altogether, these data revealed VSSP as a novel regulator of myeloid biology that mitigates MDSCs in cancer patients and reinstates a more normal myeloid phenotype that potentially favors immune activation over immune suppression.
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Carcinoma de Células Renales , Neoplasias Renales , Células Supresoras de Origen Mieloide , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/terapia , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/terapia , Células Supresoras de Origen Mieloide/fisiología , PrevalenciaRESUMEN
Proviral integration of Moloney virus 2 (PIM2) is a prosurvival factor of cancer cells and a possible therapeutic target in hematological malignancies. However, the attempts at inhibiting PIM2 have yielded underwhelming results in early clinical trials on hematological malignancies. Recently, a novel panPIM inhibitor, JP11646, was developed. The present study examined the utility of targeting PIM2 in multiple solid cancers and investigated the antitumor efficacy and the mechanisms of action of JP11646. When PIM2 expression was compared between normal and cancer tissues in publicly available datasets, PIM2 was found to be overexpressed in several types of solid cancers. PIM2 ectopic overexpression promoted tumor growth in in vivo xenograft breast cancer mouse models. The panPIM inhibitor, JP11646, suppressed in vitro cancer cell proliferation in a concentrationdependent manner in multiple types of cancers; a similar result was observed with siRNAmediated PIM2 knockdown, as well as an increased in cell apoptosis. By contrast, another panPIM inhibitor, AZD1208, suppressed the expression of downstream PIM2 targets, but not PIM2 protein expression, corresponding to no apoptosis induction. As a mechanism of PIM2 protein degradation, it was found that the proteasome inhibitor, bortezomib, reversed the apoptosis induced by JP11646, suggesting that PIM2 degradation by JP11646 is proteasomedependent. JP11646 exhibited significant anticancer efficacy with minimal toxicities at the examined doses and schedules in multiple in vivo mice xenograft solid cancer models. On the whole, the present study demonstrates that PIM2 promotes cancer progression in solid tumors. JP11646 induces apoptosis at least partly by PIM2 protein degradation and suppresses cancer cell proliferation in vitro and in vivo. JP11646 may thus be a possible treatment strategy for multiple types of solid cancers.
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Neoplasias de la Mama , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Ratones , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidoresRESUMEN
The capacity and diversity of the oncology leadership workforce has not kept pace with the emerging needs of our increasingly complex cancer centers and the spectrum of challenges our institutions face in reducing the cancer burden in diverse catchment areas. Recognizing the importance of a diverse workforce to reduce cancer inequities, the Association of American Cancer Institutes conducted a survey of its 103 cancer centers to examine diversity in leadership roles from research program leaders to cancer center directors. A total of 82 (80%) centers responded, including 64 National Cancer Institute-designated and 18 emerging centers. Among these 82 respondents, non-Hispanic White individuals comprised 79% of center directors, 82% of deputy directors, 72% of associate directors, and 72% of program leaders. Women are underrepresented in all leadership roles (ranging from 16% for center directors to 45% for associate directors). Although the limited gender, ethnic, and racial diversity of center directors and perhaps deputy directors is less surprising, the demographics of current research program leaders and associate directors exposes a substantial lack of diversity in the traditional cancer center senior leadership pipeline. Sole reliance on the cohort of current center leaders and leadership pipeline is unlikely to produce the diversity in cancer center leadership needed to facilitate the ability of those centers to address the needs of the diverse populations they serve. Informed by these data, this commentary describes some best practices to build a pipeline of emerging leaders who are representative of the diverse populations served by these institutions and who are well positioned to succeed.
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Liderazgo , Neoplasias , Femenino , Humanos , National Cancer Institute (U.S.) , Grupos Raciales , Estados UnidosRESUMEN
Multiple myeloma (MM) is an incapacitating hematological malignancy characterized by accumulation of cancerous plasma cells in the bone marrow (BM) and production of an abnormal monoclonal protein (M-protein). The BM microenvironment has a key role in myeloma development by facilitating the growth of the aberrant plasma cells, which eventually interfere with the homeostasis of the bone cells, exacerbating osteolysis and inhibiting osteoblast differentiation. Recent recognition that metabolic reprograming has a major role in tumor growth and adaptation to specific changes in the microenvironmental niche have led to consideration of the role of sphingolipids and the enzymes that control their biosynthesis and degradation as critical mediators of cancer since these bioactive lipids have been directly linked to the control of cell growth, proliferation, and apoptosis, among other cellular functions. In this review, we present the recent progress of the research investigating the biological implications of sphingolipid metabolism alterations in the regulation of myeloma development and its progression from the pre-malignant stage and discuss the roles of sphingolipids in in MM migration and adhesion, survival and proliferation, as well as angiogenesis and invasion. We introduce the current knowledge regarding the role of sphingolipids as mediators of the immune response and drug-resistance in MM and tackle the new developments suggesting the manipulation of the sphingolipid network as a novel therapeutic direction for MM.
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Despite advances in the treatment of multiple myeloma in the past decades, the disease remains incurable, and understanding signals and molecules that can control myeloma growth and survival are important for the development of novel therapeutic strategies. One such molecule, CD86, regulates multiple myeloma cell survival via its interaction with CD28 and signaling through its cytoplasmic tail. Although the CD86 cytoplasmic tail has been shown to be involved in drug resistance and can induce molecular changes in multiple myeloma cells, its function has been largely unexplored. Here, we show that CD86 cytoplasmic tail has a role in trafficking CD86 to the cell surface. This is due in part to a PDZ-binding motif at its C-terminus which is important for proper trafficking from the Golgi apparatus. BioID analysis revealed 10 PDZ domain-containing proteins proximal to CD86 cytoplasmic tail in myeloma cells. Among them, we found the planar cell polarity proteins, SCRIB and DLG1, are important for proper CD86 surface expression and the growth and survival of myeloma cells. These findings indicate a mechanism by which myeloma cells confer cellular survival and drug resistance and indicate a possible motif to target for therapeutic gain. IMPLICATIONS: These findings demonstrate the importance of proper trafficking of CD86 to the cell surface in myeloma cell survival and may provide a new therapeutic target in this disease.
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Antígeno B7-2 , Homólogo 1 de la Proteína Discs Large , Proteínas de la Membrana , Mieloma Múltiple , Proteínas Supresoras de Tumor , Antígeno B7-2/metabolismo , Antígenos CD28/metabolismo , Membrana Celular/metabolismo , Polaridad Celular , Homólogo 1 de la Proteína Discs Large/genética , Homólogo 1 de la Proteína Discs Large/metabolismo , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Dominios PDZ , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
PURPOSE: High tumor mutation burden (TMB) in many cancer types is associated with the production of tumor-specific neoantigens, a favorable outcome and response to immune checkpoint blockade (ICB) therapy. Besides mutation-derived neoantigens, aberrant intron retention also produces tumor neopeptides that could trigger an immune response. The relationship between intron-retention-derived tumor neoantigens (IR-neoAg) and clinical outcomes in pancreatic cancer remains uncertain. Here, we quantify IR-neoAg in pancreatic cancer and evaluate whether IR-neoAg load might serve as a biomarker for selecting patients who may benefit from ICB therapy. METHODS: We developed a computational approach to estimate patient-specific IR-neoAg load from transcriptome data available in The Cancer Genome Atlas pancreatic cancer cohort. Associations between IR-neoAg load and patient overall survival were evaluated using Kaplan-Meier estimates and Cox regression. Differential expression of immune checkpoint and HLA-I genes was evaluated in tumors with high IR-neoAg load. RESULTS: High IR-neoAg load predicted better overall survival in pancreatic cancer, although no association was found for TMB. IR-neoAg load remained a significant prognostic factor after adjusting for patient age, sex, tumor stage and grade, and TMB. Moreover, pancreatic tumors with both high IR-neoAg load and high HLA-I gene expression had similar gene expression profiles as other tumor types that showed response to anti-programmed cell death protein 1 therapy. CONCLUSION: IR-neoAg load is associated with favorable survival in pancreatic cancer. These findings provide strong evidence for considering IR-neoAgs when selecting patients who might benefit from ICB therapy.
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Neoplasias Pancreáticas , Humanos , Intrones , Mutación , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Pronóstico , Neoplasias PancreáticasRESUMEN
Humoral immunity is essential for protection against pathogens, emphasized by the prevention of 2-3 million deaths worldwide annually by childhood immunizations. Long-term protective immunity is dependent on the continual production of neutralizing antibodies by the subset of long-lived plasma cells (LLPCs). LLPCs are not intrinsically long-lived, but require interaction with LLPC niche stromal cells for survival. However, it remains unclear which and how these interactions sustain LLPC survival and long-term humoral immunity. We now have found that the immunosuppressive enzyme indoleamine 2,3- dioxygenase 1 (IDO1) is required to sustain antibody responses and LLPC survival. Activation of IDO1 occurs upon the engagement of CD80/CD86 on the niche dendritic cells by CD28 on LLPC. Kynurenine, the product of IDO1 catabolism, activates the aryl hydrocarbon receptor in LLPC, reinforcing CD28 expression and survival signaling. These findings expand the immune function of IDO1 and uncover a novel pathway for sustaining LLPC survival and humoral immunity.
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Células Dendríticas/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Células Plasmáticas/inmunología , Animales , Anticuerpos Neutralizantes/metabolismo , Antígeno B7-1/metabolismo , Antígenos CD28/metabolismo , Autorrenovación de las Células , Supervivencia Celular , Células Cultivadas , Femenino , Inmunidad Humoral , Memoria Inmunológica , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Ratones , Ratones NoqueadosRESUMEN
MYC activates different metabolic programs in a cell-type- and cell-status-dependent manner. However, the role of MYC in inflammatory macrophages has not yet been determined. Metabolic and molecular analyses reveal that MYC, but not hypoxia inducible factor 1 (HIF1), is involved in enhancing early glycolytic flux during inflammatory macrophage polarization. Ablation of MYC decreases lactate production by regulating lactate dehydrogenase (LDH) activity and causes increased inflammatory cytokines by regulating interferon regulatory factor 4 (IRF4) in response to lipopolysaccharide. Moreover, myeloid-specific deletion of MYC and pharmacological inhibition of the MYC/LDH axis enhance inflammation and the bacterial clearance in vivo. These results elucidate the potential role of the MYC/LDH/IRF4 axis in inflammatory macrophages by connecting early glycolysis with inflammatory responses and suggest that modulating early glycolytic flux mediated by the MYC/LDH axis can be used to open avenues for the therapeutic modulation of macrophage polarization to fight against bacterial infection.
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Glucólisis , Inflamación/metabolismo , Inflamación/patología , Factores Reguladores del Interferón/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Animales , Bacterias/metabolismo , Citocinas/biosíntesis , Femenino , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inmunidad Innata , Mediadores de Inflamación/metabolismo , Ácido Láctico/metabolismo , Lipopolisacáridos , Masculino , Ratones Noqueados , Proteínas Proto-Oncogénicas c-myc/deficienciaRESUMEN
Resistance to the proteasome inhibitor bortezomib (BTZ) represents a major obstacle in the treatment of multiple myeloma (MM). The contribution of lipid metabolism in the resistance of MM cells to BTZ is mostly unknown. Here we report that levels of fatty acid elongase 6 (ELOVL6) were lower in MM cells from BTZ-nonresponsive vs BTZ-responsive patients and in cultured MM cells selected for BTZ resistance compared with parental counterparts. Accordingly, depletion of ELOVL6 in parental MM cells suppressed BTZ-induced endoplasmic reticulum (ER) stress and cytotoxicity, whereas restoration of ELOVL6 levels in BTZ-resistant MM cells sensitized them to BTZ in tissue culture settings and, as xenografts, in a plasmacytoma mouse model. Furthermore, for the first time, we identified changes in the BTZ-induced lipidome between parental and BTZ-resistant MM cell lines underlying a functional difference in their response to BTZ. We demonstrated that restoration of ELOVL6 levels in BTZ-resistant MM cells resensitized them to BTZ largely via upregulation of ELOVL6-dependent ceramide species, which was a prerequisite for BTZ-induced ER stress and cell death in these cells. Our data characterize ELOVL6 as a major clinically relevant regulator of MM cell resistance to BTZ, which can emerge from the impaired ability of these cells to alter ceramide composition in response to BTZ.
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Mieloma Múltiple , Animales , Bortezomib/farmacología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Elongasas de Ácidos Grasos , Humanos , Ratones , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genéticaRESUMEN
Chemotherapy-induced peripheral neurotoxicity is a common dose-limiting side effect of several cancer chemotherapeutic agents, and no effective therapies exist. Here we constructed a systems pharmacology model of intracellular signaling in peripheral neurons to identify novel drug targets for preventing peripheral neuropathy associated with proteasome inhibitors. Model predictions suggested the combinatorial inhibition of TNFα, NMDA receptors, and reactive oxygen species should prevent proteasome inhibitor-induced neuronal apoptosis. Dexanabinol, an inhibitor of all three targets, partially restored bortezomib-induced reduction of proximal action potential amplitude and distal nerve conduction velocity in vitro and prevented bortezomib-induced mechanical allodynia and thermal hyperalgesia in rats, including a partial recovery of intraepidermal nerve fiber density. Dexanabinol failed to restore bortezomib-induced decreases in electrophysiological endpoints in rats, and it did not compromise bortezomib anti-cancer effects in U266 multiple myeloma cells and a murine xenograft model. Owing to its favorable safety profile in humans and preclinical efficacy, dexanabinol might represent a treatment option for bortezomib-induced neuropathic pain.
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Although plasmacytoid dendritic cells (pDCs) have been shown to play a critical role in generating viral immunity and promoting tolerance to suppress antitumor immunity, whether and how pDCs cross-prime CD8 T cells in vivo remain controversial. Using a pDC-targeted vaccine model to deliver antigens specifically to pDCs, we have demonstrated that pDC-targeted vaccination led to strong cross-priming and durable CD8 T cell immunity. Surprisingly, cross-presenting pDCs required conventional DCs (cDCs) to achieve cross-priming in vivo by transferring antigens to cDCs. Taking advantage of an in vitro system where only pDCs had access to antigens, we further demonstrated that cross-presenting pDCs were unable to efficiently prime CD8 T cells by themselves, but conferred antigen-naive cDCs the capability of cross-priming CD8 T cells by transferring antigens to cDCs. Although both cDC1s and cDC2s exhibited similar efficiency in acquiring antigens from pDCs, cDC1s but not cDC2s were required for cross-priming upon pDC-targeted vaccination, suggesting that cDC1s played a critical role in pDC-mediated cross-priming independent of their function in antigen presentation. Antigen transfer from pDCs to cDCs was mediated by previously unreported pDC-derived exosomes (pDCexos), that were also produced by pDCs under various conditions. Importantly, all these pDCexos primed naive antigen-specific CD8 T cells only in the presence of bystander cDCs, similarly to cross-presenting pDCs, thus identifying pDCexo-mediated antigen transfer to cDCs as a mechanism for pDCs to achieve cross-priming. In summary, our data suggest that pDCs employ a unique mechanism of pDCexo-mediated antigen transfer to cDCs for cross-priming.
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Linfocitos T CD8-positivos/metabolismo , Reactividad Cruzada/inmunología , Células Dendríticas/metabolismo , Exosomas/metabolismo , Animales , Presentación de Antígeno/inmunología , Linfocitos T CD8-positivos/inmunología , Células Cultivadas , Células Dendríticas/inmunología , Exosomas/inmunología , Humanos , Ratones , Ratones Endogámicos C57BLRESUMEN
Multiple myeloma (MM) is a hematological malignancy of terminally differentiated bone marrow (BM) resident B lymphocytes known as plasma cells (PC). PC that reside in the bone marrow include a distinct population of long-lived plasma cells (LLPC) that have the capacity to live for very long periods of time (decades in the human population). LLPC biology is critical for understanding MM disease induction and progression because MM shares many of the same extrinsic and intrinsic survival programs as LLPC. Extrinsic survival signals required for LLPC survival include soluble factors and cellular partners in the bone marrow microenvironment. Intrinsic programs that enhance cellular fidelity are also required for LLPC survival including increased autophagy, metabolic fitness, the unfolded protein response (UPR), and enhanced responsiveness to endoplasmic reticulum (ER) stress. Targeting LLPC cell survival mechanisms have led to standard of care treatments for MM including proteasome inhibition (Bortezomib), steroids (Dexamethasone), and immunomodulatory drugs (Lenalidomide). MM patients that relapse often do so by circumventing LLPC survival pathways targeted by treatment. Understanding the mechanisms by which LLPC are able to survive can allow us insight into the treatment of MM, which allows for the enhancement of therapeutic strategies in MM both at diagnosis and upon patient relapse.
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Durable humoral immunity against epidemic infectious disease requires the survival of long-lived plasma cells (LLPCs). LLPC longevity is dependent on metabolic programs distinct from short-lived plasma cells (SLPCs); however, the mechanistic basis for this difference is unclear. We have previously shown that CD28, the prototypic T cell costimulatory receptor, is expressed on both LLPCs and SLPCs but is essential only for LLPC survival. Here we show that CD28 transduces pro-survival signaling specifically in LLPCs through differential SLP76 expression. CD28 signaling in LLPCs increased glucose uptake, mitochondrial mass/respiration, and reactive oxygen species (ROS) production. Unexpectedly, CD28-mediated regulation of mitochondrial respiration, NF-κB activation, and survival was ROS dependent. IRF4, a target of NF-κB, was upregulated by CD28 activation in LLPCs and decreased IRF4 levels correlated with decreased glucose uptake, mitochondrial mass, ROS, and CD28-mediated survival. Altogether, these data demonstrate that CD28 signaling induces a ROS-dependent metabolic program required for LLPC survival.
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Antígenos CD28/metabolismo , Células Plasmáticas/citología , Células Plasmáticas/metabolismo , Animales , Células de la Médula Ósea/citología , Respiración de la Célula , Supervivencia Celular , Femenino , Glucosa/metabolismo , Humanos , Factores Reguladores del Interferón/metabolismo , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Bazo/citologíaRESUMEN
Multiple myeloma is a clonal disease of long-lived plasma cells and is the second most common hematological cancer behind Non-Hodgkin's Lymphoma. Malignant transformation of plasma cells imparts the ability to proliferate, causing harmful lesions in patients. In advanced stages myeloma cells become independent of their bone marrow microenvironment and form extramedullary disease. Plasma cells depend on a rich array of signals from neighboring cells within the bone marrow for survival which myeloma cells exploit for growth and proliferation. Recent evidence suggests, however, that both the myeloma cells and the microenvironment have undergone alterations as early as during precursor stages of the disease. There are no current therapies routinely used for treating myeloma in early stages, and while recent therapeutic efforts have improved patients' median survival, most will eventually relapse. This is due to mutations in myeloma cells that not only allow them to utilize its bone marrow niche but also facilitate autocrine pro-survival signaling loops for further progression. This review will discuss the stages of myeloma cell progression and how myeloma cells progress within and outside of the bone marrow microenvironment.
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Durable humoral immunity is dependent upon the generation of antigen-specific antibody titers, produced by non-proliferating bone marrow resident long-lived plasma cells (LLPC). Longevity is the hallmark of LLPC, but why and how they survive and function for years after antigen exposure is only beginning to be understood. LLPC are not intrinsically long-lived; they require continuous signals from the LLPC niche to survive. Signals unique to LLPC survival (vs. PC survival in general) most notably include those that upregulate the anti-apoptotic factor Mcl-1 and activation of the CD28 receptor expressed on LLPC. Other potential factors include expression of BCMA, upregulation of the transcription factor ZBTB20, and upregulation of the enzyme ENPP1. Metabolic fitness is another key component of LLPC longevity, facilitating the diversion of glucose to generate pyruvate during times of stress to facilitate long term survival. A third major component of LLPC survival is the microenvironment/LLPC niche itself. Cellular partners such as stromal cells, dendritic cells, and T regulatory cells establish a niche for LLPC and drive survival signaling by expressing ligands such as CD80/CD86 for CD28 and producing soluble and stromal factors that contribute to LLPC longevity. These findings have led to the current paradigm wherein both intrinsic and extrinsic mechanisms are required for the survival of LLPC. Here we outline this diverse network of signals and highlight the mechanisms thought to regulate and promote the survival of LLPC. Understanding this network of signals has direct implications in increasing our basic understanding of plasma cell biology, but also in vaccine and therapeutic drug development to address the pathologies that can arise from this subset.
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Células Plasmáticas/inmunología , Animales , Subgrupos de Linfocitos B/inmunología , Humanos , TranscriptomaRESUMEN
Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is the central transcriptional regulator of the xenobiotic response. Our study revealed that AHR also positively regulates intracellular polyamine production via direct transcriptional activation of 2 genes, ODC1 and AZIN1, which are involved in polyamine biosynthesis and control, respectively. In patients with multiple myeloma (MM), AHR levels were inversely correlated with survival, suggesting that AHR inhibition may be beneficial for the treatment of this disease. We identified clofazimine (CLF), an FDA-approved anti-leprosy drug, as a potent AHR antagonist and a suppressor of polyamine biosynthesis. Experiments in a transgenic model of MM (Vk*Myc mice) and in immunocompromised mice bearing MM cell xenografts revealed high efficacy of CLF comparable to that of bortezomib, a first-in-class proteasome inhibitor used for the treatment of MM. This study identifies a previously unrecognized regulatory axis between AHR and polyamine metabolism and reveals CLF as an inhibitor of AHR and a potentially clinically relevant anti-MM agent.