RESUMO
Neutrophils are the most abundant peripheral immune cells and thus, are continually replenished by bone marrow-derived progenitors. Still, how newly identified neutrophil subsets fit into the bone marrow neutrophil lineage remains unclear. Here, we use mass cytometry to show that two recently defined human neutrophil progenitor populations contain a homogeneous progenitor subset we term "early neutrophil progenitors" (eNePs) (Lin-CD66b+CD117+CD71+). Surface marker- and RNA-expression analyses, together with in vitro colony formation and in vivo adoptive humanized mouse transfers, indicate that eNePs are the earliest human neutrophil progenitors. Furthermore, we identified CD71 as a marker associated with the earliest neutrophil developmental stages. Expression of CD71 marks proliferating neutrophils, which were expanded in the blood of melanoma patients and detectable in blood and tumors from lung cancer patients. In summary, we establish CD117+CD71+ eNeP as the inceptive human neutrophil progenitor and propose a refined model of the neutrophil developmental lineage in bone marrow.
Assuntos
Antígenos CD/metabolismo , Células da Medula Óssea/citologia , Células Progenitoras Mieloides/metabolismo , Neutrófilos/citologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores da Transferrina/metabolismo , Transferência Adotiva , Animais , Medula Óssea/metabolismo , Linhagem da Célula , Humanos , Masculino , Melanoma/sangue , Camundongos , Camundongos Endogâmicos NOD , Células Progenitoras Mieloides/citologiaRESUMO
BACKGROUND AND AIMS: Programmed death 1 (PD-1) checkpoint inhibition has shown promising results in patients with hepatocellular carcinoma, inducing objective responses in approximately 20% of treated patients. The roles of other coinhibitory molecules and their individual contributions to T-cell dysfunction in liver cancer, however, remain largely elusive. APPROACH AND RESULTS: We performed a comprehensive mRNA profiling of cluster of differentiation 8 (CD8) T cells in a murine model of autochthonous liver cancer by comparing the transcriptome of naive, functional effector, and exhausted, tumor-specific CD8 T cells. Subsequently, we functionally validated the role of identified genes in T-cell exhaustion. Our results reveal a unique transcriptome signature of exhausted T cells and demonstrate that up-regulation of the inhibitory immune receptor T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitor motif domains (TIGIT) represents a hallmark in the process of T-cell exhaustion in liver cancer. Compared to PD-1, expression of TIGIT more reliably identified exhausted CD8 T cells at different stages of their differentiation. In combination with PD-1 inhibition, targeting of TIGIT with antagonistic antibodies resulted in synergistic inhibition of liver cancer growth in immunocompetent mice. Finally, we demonstrate expression of TIGIT on tumor-infiltrating CD8 T cells in tissue samples of patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma and identify two subsets of patients based on differential expression of TIGIT on tumor-specific T cells. CONCLUSIONS: Our transcriptome analysis provides a valuable resource for the identification of key pathways involved in T-cell exhaustion in patients with liver cancer and identifies TIGIT as a potential target in checkpoint combination therapies.
Assuntos
Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Colangiocarcinoma/genética , Colangiocarcinoma/imunologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Receptores Imunológicos/genética , Transcriptoma , Idoso , Animais , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/patologia , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores Imunológicos/antagonistas & inibidores , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacosRESUMO
The role of nonclassical, patrolling monocytes in lung tumor metastasis and their functional relationships with other immune cells remain poorly defined. Contributing to these gaps in knowledge is a lack of cellular specificity in commonly used approaches for depleting nonclassical monocytes. To circumvent these limitations and study the role of patrolling monocytes in melanoma metastasis to lungs, we generated C57BL/6J mice in which the Nr4a1 superenhancer E2 subdomain is ablated (E2 -/- mice). E2 -/- mice lack nonclassical patrolling monocytes but preserve classical monocyte and macrophage numbers and functions. Interestingly, NK cell recruitment and activation were impaired, and metastatic burden was increased in E2 -/-mice. E2 -/- mice displayed unchanged "educated" (CD11b+CD27+) and "terminally differentiated" (CD11b+CD27-) NK cell frequencies. These perturbations were accompanied by reduced expression of stimulatory receptor Ly49D on educated NK cells and increased expression of inhibitory receptor NKG2A/CD94 on terminally differentiated NK cells. Thus, our work demonstrates that patrolling monocytes play a critical role in preventing lung tumor metastasis via NK cell recruitment and activation.
Assuntos
Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Monócitos/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Animais , Linhagem Celular Tumoral , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered to be a metabolic predisposition to liver cancer. However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here we show, in mouse models and human samples, that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4(+) but not CD8(+) T lymphocytes, leading to accelerated hepatocarcinogenesis. We also demonstrate that CD4(+) T lymphocytes have greater mitochondrial mass than CD8(+) T lymphocytes and generate higher levels of mitochondrially derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4(+) T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4(+) T lymphocyte decrease and delayed NAFLD-promoted HCC. Our results provide an unexpected link between lipid dysregulation and impaired anti-tumour surveillance.
Assuntos
Linfócitos T CD4-Positivos/patologia , Carcinogênese , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinogênese/imunologia , Carcinogênese/patologia , Carcinoma Hepatocelular/metabolismo , Estudos de Casos e Controles , Colina/metabolismo , Dieta , Modelos Animais de Doenças , Genes myc , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Ácido Linoleico/metabolismo , Metabolismo dos Lipídeos , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Masculino , Metionina/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive liver tumor with a poor 5-year survival rate. Many HCCs are not amenable to surgical resection, because of tumor size, location, or because of the patient's poor liver function, a common obstacle to HCC therapy, because HCCs almost always develop in chronically inflamed livers. SUMMARY: In recent years, many efforts have been made to improve patient survival by conducting clinical trials investigating local and systemic treatment options for patients with unresectable tumors. These treatment options include radiofrequency ablation (RFA), transarterial chemoembolization (TACE), selective internal radiotherapy with yttrium-90 (SIRT), stereotactic body radiation therapy (SBRT), proton beam therapy, molecular targeted therapy, and checkpoint inhibition. In this "to-the-point" article, we review the current standard and summarize the most recent findings in unresectable HCC treatment. KEY POINTS: (1) RFA is currently the preferred treatment for patients with tumor burden restricted to the liver and not eligible for surgical resection; (2) TACE is utilized in patients who are not eligible for RFA because of tumor location and/or number of tumor lesions; (3) SIRT might improve treatment responses achieved by TACE and is feasible in patients with portal vein thrombosis; (4) new radiation therapy treatment modalities such as SBRT and proton beam therapy show promising results for local tumor control; and (5) sorafenib remains the first-line systemic treatment option after several large clinical trials have failed to show superiority of other molecular targeted therapies in HCC patients.
Assuntos
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Guias de Prática Clínica como Assunto , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Ablação por Cateter/métodos , Ablação por Cateter/normas , Ablação por Cateter/tendências , Quimioembolização Terapêutica/métodos , Quimioembolização Terapêutica/normas , Quimioembolização Terapêutica/tendências , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Terapia Combinada/normas , Terapia Combinada/tendências , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/normas , Terapia de Alvo Molecular/tendências , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Terapia com Prótons/métodos , Terapia com Prótons/normas , Terapia com Prótons/tendências , Radiocirurgia/métodos , Radiocirurgia/normas , Radiocirurgia/tendências , Radioterapia/métodos , Radioterapia/normas , Radioterapia/tendências , Sorafenibe , Taxa de Sobrevida , Resultado do Tratamento , Carga Tumoral , Radioisótopos de Ítrio/administração & dosagemRESUMO
UNLABELLED: Hepatocellular carcinoma (HCC) patients suffer from a poor survival rate and a high incidence of postoperative recurrence. The hepatic microenvironment plays a significant role in the initiation, progression, and recurrence of HCC; however, the causal mechanisms of these phenomena are unclear. Given the predominant underlying fibrotic and cirrhotic conditions of the liver prone to HCC and its recurrence, alterations of components of the inflammatory milieu have been suggested as factors that promote HCC development. In particular, activated hepatic stellate cells (A-HSCs), which play a key role in liver fibrosis and cirrhosis, have been suggested as contributors to the HCC-prone microenvironment. Here, we have identified and validated an A-HSC-specific gene expression signature among nontumor tissues of 319 HCC patients that is significantly and independently associated with HCC recurrence and survival. Peritumoral, rather than tumor tissue-related, A-HSC-specific gene expression is associated with recurrence and poor survival. Analyses of A-HSC-specific gene signatures and further immunohistochemical validation in an additional 143 HCC patients have revealed that A-HSCs preferentially affect monocyte populations, shifting their gene expression from an inflammatory to an immunosuppressive signature. In addition, the interaction between A-HSCs and monocytes induces protumorigenic and progressive features of HCC cells by enhancing cell migration and tumor sphere formation. CONCLUSION: A-HSCs play a significant role in promoting HCC progression through interaction with and alteration of monocyte activities within the liver microenvironment; thus, disrupting the interactions and signaling events between the inflammatory milieu and components of the microenvironment may be useful therapeutic strategies for preventing HCC tumor relapse.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Comunicação Celular , Células Estreladas do Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Monócitos/metabolismo , Idoso , Análise de Variância , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Movimento Celular , Feminino , Células Estreladas do Fígado/patologia , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Análise Multivariada , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Análise de Sobrevida , Células Tumorais Cultivadas , Microambiente TumoralRESUMO
Myeloid-derived suppressor cells are key components of tumor-induced immune suppression. They are composed of a heterogeneous population of immature myeloid cells that abrogates innate and adaptive immune responses. Myeloid-derived suppressor cells accumulate not only in peripheral blood, secondary lymphoid organs and tumors, but also in the liver in preclinical tumor models and in hepatocellular carcinoma patients. The liver, continuously exposed to food and microbial antigens from the intestine, avoids autoimmune damage through the use of specialized mechanisms of immune tolerance. In the context of cancer, myeloid-derived suppressor cells profit the intrinsic tolerogenic properties of the liver to accumulate and exert various immune-suppressive and tumor-promoting mechanisms which go from inducing immune cell dysfunction to supporting the generation of liver metastases. In this review, we seek to describe the phenotype, function, accumulation and therapeutic targeting of hepatic myeloid-derived suppressor cells both in preclinical settings and in the context of human hepatocellular carcinoma.
Assuntos
Carcinoma Hepatocelular/imunologia , Tolerância Imunológica , Terapia de Imunossupressão , Neoplasias Hepáticas/imunologia , Células Mieloides/imunologia , Animais , Carcinoma Hepatocelular/patologia , Humanos , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/patologia , Células Mieloides/patologia , Metástase Neoplásica , Evasão TumoralRESUMO
PURPOSE: Safety and efficacy of acapatamab, a prostate-specific membrane antigen (PSMA) x CD3 bispecific T-cell engager were evaluated in a first-in-human study in metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Patients with mCRPC refractory to androgen receptor pathway inhibitor therapy and taxane-based chemotherapy received target acapatamab doses ranging from 0.003 to 0.9 mg in dose exploration (seven dose levels) and 0.3 mg (recommended phase II dose) in dose expansion intravenously every 2 weeks. Safety (primary objective), pharmacokinetics, and antitumor activity (secondary objectives) were assessed. RESULTS: In all, 133 patients (dose exploration, n = 77; dose expansion, n = 56) received acapatamab. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event seen in 97.4% and 98.2% of patients in dose exploration and dose expansion, respectively; grade ≥ 3 was seen in 23.4% and 16.1%, respectively. Most CRS events were seen in treatment cycle 1; incidence and severity decreased at/beyond cycle 2. In dose expansion, confirmed prostate-specific antigen (PSA) responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (Response Evaluation Criteria in Solid Tumors 1.1). Median PSA progression-free survival (PFS) was 3.3 months [95% confidence interval (CI): 3.0-4.9], radiographic PFS per Prostate Cancer Clinical Trials Working Group 3 was 3.7 months (95% CI: 2.0-5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24 hours of initiation. Treatment-emergent antidrug antibodies were detected in 55% and impacted serum exposures in 36% of patients in dose expansion. CONCLUSIONS: Acapatamab was safe and tolerated and had a manageable CRS profile. Preliminary signs of efficacy with limited durable antitumor activity were observed. Acapatamab demonstrated pharmacokinetic and pharmacodynamic activity.
Assuntos
Antineoplásicos , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/patologia , Antígeno Prostático Específico , Meia-Vida , Resultado do Tratamento , Antineoplásicos/uso terapêutico , Antagonistas de Receptores de Andrógenos/uso terapêutico , Linfócitos T/metabolismoRESUMO
Introduction: In oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and attention ascribed to ADAs in oncology clinical studies have therefore been limited, and the extant literature on this subject scarce. In recent years, T cell engagers have gained preeminence within the prolific field of cancer immunotherapy. These drugs whose mode of action is expected to potently stimulate anti-tumor immunity, may potentially induce ADAs as an unintended corollary due to an overall augmentation of the immune response. ADA formation is therefore emerging as an important determinant in the successful clinical development of such biologics. Methods: Here we describe the immunogenicity and its impact observed to pasotuxizumab (AMG 212), a prostate-specific membrane antigen (PSMA)-targeting bispecific T cell engager (BiTE®) molecule in NCT01723475, a first-in-human (FIH), multicenter, dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC). To explain the disparity in ADA incidence observed between the SC and CIV arms of the study, we interrogated other patient and product-specific factors that may have explained the difference beyond the route of administration. Results: Treatment-emergent ADAs (TE-ADA) developed in all subjects treated with at least 1 cycle of AMG 212 in the subcutaneous (SC) arm. These ADAs were neutralizing and resulted in profound exposure loss that was associated with contemporaneous reversal of initial Prostate Surface Antigen (PSA) responses, curtailing durability of PSA response in patients. Pivoting from SC to a continuous intravenous (CIV) administration route remarkably yielded no subjects developing ADA to AMG 212. Through a series of stepwise functional assays, our investigation revealed that alongside a more historically immunogenic route of administration, non-tolerant T cell epitopes within the AMG 212 amino acid sequence were likely driving the high-titer, sustained ADA response observed in the SC arm. Discussion: These mechanistic insights into the AMG 212 ADA response underscore the importance of performing preclinical immunogenicity risk evaluation as well as advocate for continuous iteration to better our biologics.
Assuntos
Produtos Biológicos , Próstata , Masculino , Humanos , Análise de Causa Fundamental , Antígeno Prostático Específico/metabolismo , Anticorpos/metabolismo , Antígenos de Superfície/metabolismo , Linfócitos TRESUMO
BACKGROUND: Understanding neutrophil heterogeneity and its relationship to disease progression has become a recent focus of cancer research. Indeed, several studies have identified neutrophil subpopulations associated with protumoral or antitumoral functions. However, this work has been hindered by a lack of widely accepted markers with which to define neutrophil subpopulations. METHODS: To identify markers of neutrophil heterogeneity in cancer, we used single-cell cytometry by time-of-flight (CyTOF) coupled with high-dimensional analysis on blood samples from treatment-naïve patients with melanoma. RESULTS: Our efforts allowed us to identify seven blood neutrophil clusters, including two previously identified individual populations. Interrogation of these neutrophil subpopulations revealed a positive trend between specific clusters and disease stage. Finally, we recapitulated these seven blood neutrophil populations via flow cytometry and found that they exhibited diverse capacities for phagocytosis and reactive oxygen species production in vitro. CONCLUSIONS: Our data provide a refined consensus on neutrophil heterogeneity markers, enabling a prospective functional evaluation in patients with solid tumors.
Assuntos
Citometria de Fluxo/métodos , Melanoma/sangue , Neutrófilos/metabolismo , Fenótipo , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Adulto JovemRESUMO
The tumor microenvironment (TME) in the liver plays an important role in primary and metastatic liver tumor formation and tumor growth promotion. Cellular and non-cellular components of the TME significantly influence tumor development, growth, metastatic spread, anti-tumor immunity and response to tumor therapy. The cellular components of the TME in the liver not only consist of infiltrating immune cells, but also of liver-resident cells such as liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC), which promote tumor growth by negatively regulating tumor-associated immune responses. In this review, we characterize cells of the TME with pro- and anti-tumor function in primary and metastatic liver tumors. Furthermore, we summarize mechanisms that permit growth of hepatic tumors despite the occurrence of spontaneous anti-tumor immune responses and how novel therapeutic approaches targeting the TME could unleash tumor-specific immune responses to improve survival of liver cancer patients.
Assuntos
Neoplasias Hepáticas/patologia , Terapia de Alvo Molecular , Microambiente Tumoral , Animais , Células Endoteliais/metabolismo , Células Estreladas do Fígado/metabolismo , Humanos , Imunoterapia/métodos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Taxa de SobrevidaRESUMO
Cellular senescence is a stress-induced cell-cycle arrest program that prevents malignant transformation of senescent cells following oncogenic pathway activation and DNA damage. Senescent cells are metabolically active and secrete cytokines and chemokines that shape the function and composition of their microenvironment. These cytokines can recruit immune cells such as lymphocytes and myeloid cells that depending on the context can either promote or inhibit liver tumor development and progression. Accordingly, pharmacologically targeting of secreted cytokines or reprogramming the expression of these cytokines in senescent cells represents a promising approach to skew senescence-associated immune responses toward cancer cell killing.
RESUMO
Oncogene-induced senescence causes hepatocytes to secrete cytokines, which induce their immune-mediated clearance to prevent tumor initiation, a process termed "senescence surveillance." However, senescent hepatocytes give rise to hepatocellular carcinomas (HCCs), if the senescence program is bypassed or if senescent cells are not cleared. Here, we show context-specific roles for CCR2+ myeloid cells in liver cancer. Senescence surveillance requires the recruitment and maturation of CCR2+ myeloid cells, and CCR2 ablation caused outgrowth of HCC. In contrast, HCC cells block the maturation of recruited myeloid precursors, which, through NK cell inhibition, promote growth of murine HCC and worsen the prognosis and survival of human HCC patients. Thus, while senescent hepatocyte-secreted chemokines suppress liver cancer initiation, they may accelerate the growth of fully established HCC.
Assuntos
Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Animais , Carcinoma Hepatocelular/patologia , Senescência Celular/imunologia , Progressão da Doença , Feminino , Humanos , Vigilância Imunológica , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Immune-stimulatory mAbs are currently being evaluated as antitumor agents. Although overall toxicity from these agents appears to be moderate, liver toxicities have been reported and are not completely understood. We studied the effect of systemic CD40 antibody treatment on myeloid cells in the spleen and liver. Naïve and tumor-bearing mice were treated systemically with agonistic anti-CD40 antibody. Immune cell subsets in the liver and spleen, serum transaminases, and liver histologies were analyzed after antibody administration. Nox2(-/-), Cd40(-/-), and bone marrow chimeric mice were used to study the mechanism by which agonistic anti-CD40 mediates its effects in vivo. Suppressor function of murine and human tumor-induced myeloid-derived suppressor cells (MDSC) was studied upon CD40 ligation. Agonistic CD40 antibody caused liver damage within 24 hours after injection in two unrelated tumor models and mice strains. Using bone marrow chimeras, we demonstrate that CD40 antibody-induced hepatitis in tumor-bearing mice was dependent on the presence of CD40-expressing hematopoietic cells. Agonistic CD40 ligation-dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80-positive and CD40-positive liver CD11b(+)Gr-1(+) immature myeloid cells. CD40 ligation on tumor-induced murine and human CD14(+)HLA-DR(low) peripheral blood mononuclear cells from patients with cancer reduced their immune suppressor function. Collectively, agonistic CD40 antibody treatment activated tumor-induced myeloid cells, caused myeloid-dependent hepatotoxicity, and ameliorated the suppressor function of murine and human MDSC. Collectively, our data suggest that CD40 may mature immunosuppressive myeloid cells and thereby cause liver damage in mice with an accumulation of tumor-induced hepatic MDSC.
Assuntos
Anticorpos Monoclonais , Antígenos CD40/antagonistas & inibidores , Células Mieloides/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Aspartato Aminotransferases/sangue , Antígenos CD40/imunologia , Linhagem Celular Tumoral , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Feminino , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Mieloides/imunologia , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Baço/citologia , Baço/efeitos dos fármacosRESUMO
Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC) not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL), while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU) treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage.
Assuntos
Fígado/imunologia , Fígado/patologia , Células Mieloides/imunologia , Neoplasias/imunologia , Animais , Antígenos de Superfície/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Imunofenotipagem , Fígado/metabolismo , Melanoma Experimental , Camundongos , Células Mieloides/metabolismo , Neoplasias/sangue , Neoplasias/metabolismo , Fenótipo , Transaminases/sangueRESUMO
OBJECTIVE: Epidemiological and clinical information on fibrolamellar hepatocellular carcinoma (fHCC) is scarce. We performed a Surveillance, Epidemiology and End Results (SEER) database analysis with the aim of collecting information to better understand the biology and clinical aspects of this rare disease. DESIGN: Incidence trends, race- and age-specific rates, tumor size, first course surgery and five-year relative survival of 191 US cases (SEER) diagnosed with fHCC during 2000-2010 were compared to cases with hepatocellular carcinoma (HCC), HCC-not otherwise specified (HCC-NOS) and other HCC-types. RESULTS: While HCC-NOS incidence rates increased by 5.2% annually from 2000-2008 (p < 0.05) before leveling, the 1.3% change in fHCC incidence was not statistically significant. The rates of fHCC were similar across ethnic groups while HCC-NOS incidence rates were higher among non-whites. Although 16% of fHCC patients had primary tumors ≤5 cm compared to 37% of HCC-NOS cases five-year survival was better among fHCC (34%) than HCC-NOS cases (16%). Fibrolamellar HCC cases of 0-39 years of age were more likely to receive radiofrequency ablation, transplant or resection than HCC-NOS cases of that age. Survival was similar among fibrolamellar and HCC-NOS cases receiving surgery. CONCLUSION: In this largest case series, fibrolamellar and HCC-NOS age- and race-specific incidence rates and time trends differed. Despite larger tumor size than HCC-NOS cases fibrolamellar cases received surgery more often and had better survival rates. Differences in co-morbidity may influence treatment. Studies of fHCC biology, including by age, are recommended.