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Effector T cells and fibroblasts are major components in the tumor microenvironment. The means through which these cellular interactions affect chemoresistance is unclear. Here, we show that fibroblasts diminish nuclear accumulation of platinum in ovarian cancer cells, resulting in resistance to platinum-based chemotherapy. We demonstrate that glutathione and cysteine released by fibroblasts contribute to this resistance. CD8(+) T cells abolish the resistance by altering glutathione and cystine metabolism in fibroblasts. CD8(+) T-cell-derived interferon (IFN)γ controls fibroblast glutathione and cysteine through upregulation of gamma-glutamyltransferases and transcriptional repression of system xc(-) cystine and glutamate antiporter via the JAK/STAT1 pathway. The presence of stromal fibroblasts and CD8(+) T cells is negatively and positively associated with ovarian cancer patient survival, respectively. Thus, our work uncovers a mode of action for effector T cells: they abrogate stromal-mediated chemoresistance. Capitalizing upon the interplay between chemotherapy and immunotherapy holds high potential for cancer treatment.
Assuntos
Linfócitos T CD8-Positivos/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Feminino , Fibroblastos/metabolismo , Glutationa/metabolismo , Humanos , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos NusRESUMO
Live regulatory T cells (Treg cells) suppress antitumor immunity, but how Treg cells behave in the metabolically abnormal tumor microenvironment remains unknown. Here we show that tumor Treg cells undergo apoptosis, and such apoptotic Treg cells abolish spontaneous and PD-L1-blockade-mediated antitumor T cell immunity. Biochemical and functional analyses show that adenosine, but not typical suppressive factors such as PD-L1, CTLA-4, TGF-ß, IL-35, and IL-10, contributes to apoptotic Treg-cell-mediated immunosuppression. Mechanistically, apoptotic Treg cells release and convert a large amount of ATP to adenosine via CD39 and CD73, and mediate immunosuppression via the adenosine and A2A pathways. Apoptosis in Treg cells is attributed to their weak NRF2-associated antioxidant system and high vulnerability to free oxygen species in the tumor microenvironment. Thus, the data support a model wherein tumor Treg cells sustain and amplify their suppressor capacity through inadvertent death via oxidative stress. This work highlights the oxidative pathway as a metabolic checkpoint that controls Treg cell behavior and affects the efficacy of therapeutics targeting cancer checkpoints.
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Apoptose/imunologia , Antígeno B7-H1/metabolismo , Tolerância Imunológica/imunologia , Neoplasias Ovarianas/imunologia , Estresse Oxidativo/fisiologia , Linfócitos T Reguladores/imunologia , 5'-Nucleotidase/genética , 5'-Nucleotidase/metabolismo , Adenosina/metabolismo , Animais , Antígenos CD/metabolismo , Apirase/metabolismo , Antígeno CTLA-4/metabolismo , Feminino , Proteínas Ligadas por GPI/genética , Humanos , Interleucina-10/metabolismo , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Oxigênio/metabolismo , Receptor A2A de Adenosina/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral/imunologiaRESUMO
Aerobic glycolysis regulates T cell function. However, whether and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity in cancer patients remains a question. Here we found that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNAs miR-101 and miR-26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, small hairpin RNA-mediated knockdown of human EZH2 in T cells elicited poor antitumor immunity. EZH2(+)CD8(+) T cells were associated with improved survival in patients. Together, these data unveil a metabolic target and mechanism of cancer immune evasion.
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Regulação Neoplásica da Expressão Gênica/imunologia , MicroRNAs , Neoplasias/imunologia , Complexo Repressor Polycomb 2/imunologia , Linfócitos T/imunologia , Evasão Tumoral/imunologia , Animais , Separação Celular , Imunoprecipitação da Cromatina , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Citometria de Fluxo , Imunofluorescência , Glicólise , Humanos , Immunoblotting , Melanoma Experimental/imunologia , Camundongos Endogâmicos C57BL , Neoplasias Ovarianas/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Análise Serial de Tecidos , TransfecçãoRESUMO
Naive T cells are thought to be functionally quiescent. In this study, we studied and compared the phenotype, cytokine profile, and potential function of human naive CD4+ T cells in umbilical cord and peripheral blood. We found that naive CD4+ T cells, but not memory T cells, expressed high levels of chemokine CXCL8. CXCL8+ naive T cells were preferentially enriched CD31+ T cells and did not express T cell activation markers or typical Th effector cytokines, including IFN-γ, IL-4, IL-17, and IL-22. In addition, upon activation, naive T cells retained high levels of CXCL8 expression. Furthermore, we showed that naive T cell-derived CXCL8 mediated neutrophil migration in the in vitro migration assay, supported tumor sphere formation, and promoted tumor growth in an in vivo human xenograft model. Thus, human naive T cells are phenotypically and functionally heterogeneous and can carry out active functions in immune responses.
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Células Sanguíneas/fisiologia , Interleucina-8/metabolismo , Neoplasias Experimentais/imunologia , Neutrófilos/fisiologia , Linfócitos T/fisiologia , Cordão Umbilical/patologia , Animais , Carcinogênese , Linhagem Celular Tumoral , Movimento Celular , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Interleucina-8/genética , Ativação Linfocitária , Camundongos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Although immune-based therapy has proven efficacious for some patients with microsatellite instability (MSI) colon cancers, a majority of patients receive limited benefit. Conversely, select patients with microsatellite stable (MSS) tumors respond to checkpoint blockade, necessitating novel ways to study the immune tumor microenvironment (TME). We used phenotypic and spatial data from infiltrating immune and tumor cells to model cellular mixing to predict disease specific outcomes in patients with colorectal liver metastases. METHODS: Formalin fixed paraffin embedded metastatic colon cancer tissue from 195 patients were subjected to multiplex immunohistochemistry (mfIHC). After phenotyping, the G-function was calculated for each patient and cell type. Data was correlated with clinical outcomes and survival. RESULTS: High tumor cell to cytotoxic T lymphocyte (TC-CTL) mixing was associated with both a pro-inflammatory and immunosuppressive TME characterized by increased CTL infiltration and PD-L1+ expression, respectively. Presence and engagement of antigen presenting cells (APC) and helper T cells (Th) were associated with greater TC-CTL mixing and improved 5-year disease specific survival compared to patients with a low degree of mixing (42% vs. 16%, p = 0.0275). Comparison of measured mixing to a calculated theoretical random mixing revealed that PD-L1 expression on APCs resulted in an environment where CTLs were non-randomly less associated with TCs, highlighting their biologic significance. CONCLUSION: Evaluation of immune interactions within the TME of metastatic colon cancer using mfIHC in combination with mathematical modeling characterized cellular mixing of TCs and CTLs, providing a novel strategy to better predict clinical outcomes while identifying potential candidates for immune based therapies.
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Células Apresentadoras de Antígenos/imunologia , Antígeno B7-H1/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Hepáticas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Modelos Teóricos , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/imunologia , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
Immune phenomena during the preimplantation period of pregnancy are poorly understood. The aim of our study was to assess the capacity for antigen presentation of splenic antigen-presenting cells (APCs) derived from pregnant and pseudopregnant mice in in vitro conditions. Therefore, sorted CD11c(+) dendritic cells and macrophages F4/80(+) and CD11b(+) presenting ovalbumin (OVA) were cocultured with CD4(+) T cells derived from OT-II mice's (C57BL6/J-Tg(TcraTcrb)1100Mjb/J) spleen. After 132 hours of cell culture, proliferation of lymphocytes (ELISA-BrdU), activation of these cells (flow cytometry), cytokine profile (ELISA), and influence of costimulatory molecules blocking on these parameters were measured. We did not detect any differences in regulation of Th1/Th2 cytokine balance. CD86 seems to be the main costimulatory molecule involved in the proliferation response but CD80 is the main costimulatory molecule influencing cytokine secretion in pregnant mice. In conclusion, this study showed that CD80 and CD86 costimulatory molecules regulate OT-II CD4(+) T lymphocyte proliferation and cytokine response in cocultures with antigen-presenting cells derived from pregnant and pseudopregnant mice. The implications of these changes still remain unclear.
Assuntos
Células Apresentadoras de Antígenos/citologia , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Linfócitos T CD4-Positivos/citologia , Proliferação de Células , Citocinas/imunologia , Animais , Técnicas de Cocultura , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Fenótipo , Gravidez , Prenhez , Baço/citologia , Células Th1/citologia , Células Th2/citologiaRESUMO
Wound healing is an intensely studied topic involved in many relevant pathophysiological processes, including fibrosis. Despite the large interest in fibrosis, the network that is related to commensal microbiota and skin fibrosis remains mysterious. Here, we pay attention to keloid, a classical yet intractable skin fibrotic disease to establish the association between commensal microbiota to scaring tissue. Our histological data reveal the presence of microbiota in the keloids. 16S rRNA sequencing characterizes microbial composition and divergence between the pathological and normal skin tissues. Moreover, the data show elevation of interleukin-8 (IL-8) in both the circulation and keloid tissue, which elicited the collagen accumulation and migratory program of dermal fibroblasts via CXCR1/2 receptor. Our research provides insights into the pathology of human fibrotic diseases, advocating commensal bacteria and IL-8 signaling as useful targets in future interventions of recurrent keloid disease.
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Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c+ cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of Pikfyve in CD11c+ cells and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c+ cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.
Assuntos
Antígeno CD11c , Células Dendríticas , Morfolinas , Fosfatidilinositol 3-Quinases , Animais , Feminino , Humanos , Camundongos , Antígeno CD11c/metabolismo , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/efeitos dos fármacos , Hidrazonas , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Neoplasias/imunologia , Neoplasias/genética , Neoplasias/terapia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas , Linfócitos T/imunologia , MasculinoRESUMO
The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-κB pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.
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BACKGROUND: The peroral "pull" technique and the direct "push" procedure are the two main methods for percutaneous endoscopic gastrostomy (PEG) placement. Although pull-PEG is generally recommended as the first-line modality, many oncological patients require a push-PEG approach to prevent tumor seeding or overcome tumor-related obstruction. OBJECTIVE: We aimed to compare the efficacy and safety of both PEG procedures in cancer patients. METHODS: We retrospectively analyzed all consecutive PEG procedures within a tertiary oncological center. Patients were followed up with the hospital databases and National Cancer Registry to assess the technical success rate for PEG placement, the rate of minor and major adverse events (AEs), and 30-day mortality rates. We compared those outcomes between the two PEG techniques. Finally, risk factors for PEG-related adverse events were analyzed using a multivariable Cox proportional-hazard regression model adjusted for patients' sex, age, performance status (ECOG), Body Mass Index (BMI), diabetes, chemoradiotherapy (CRT) status (pre-/current-/post-treatment), and type of PEG. RESULTS: We included 1055 PEG procedures (58.7% push-PEG/41.4% pull-PEG) performed in 994 patients between 2014 and 2021 (mean age 62.0 [±10.7] yrs.; 70.2% males; indication: head-and-neck cancer 75.9%/other cancer 24.1%). The overall technical success for PEG placement was 96.5%. Although the "push" technique had a higher rate of all AEs (21.4% vs. 7.1%, Hazard Ratio [HR] = 2.9; 95% CI = 1.9-4.3, p < 0.001), most of these constituted minor AEs (71.9%), such as tube dislodgement. The methods had no significant difference regarding major AEs and 30-day mortality rates. Previous CRT was associated with an increased risk of major AEs (hazard ratio = 2.7, 95% CI = 1.0-7.2, p = 0.042). CONCLUSION: The risk of major AEs was comparable between the push- and pull-PEG techniques in cancer patients. Due to frequent tube dislodgement in push-PEG, the pull technique may be more suitable for long-term feeding. Previous CRT increases the risk of major AEs, favoring early ("prophylactic") PEG placement when such treatment is expected.
Assuntos
Gastrostomia , Neoplasias de Cabeça e Pescoço , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Gastrostomia/efeitos adversos , Gastrostomia/métodos , Estudos Retrospectivos , Neoplasias de Cabeça e Pescoço/cirurgia , Neoplasias de Cabeça e Pescoço/etiologia , Auditoria ClínicaRESUMO
Success of pregnancy depends on many factors. Three phenomena inducing immune tolerance against semi-allogeneic conceptus may play a crucial role in the pre-implantation period of pregnancy: influence of sex hormones in sex cycle, presence of oocyte or embryo and the presence of semen in the female reproductive tract. On the other hand dendritic cells are the most effective antigen-presenting cells in regulation of immune phenomena and also are considered as potent participants in inducing immune tolerance in the pregnancy. They communicate with T cells in cell contact-dependent manner or via cytokines. During cell-cell contacts, costimulatory molecules play a key role and their expression is often dependent on cytokines milieu. Both costimulatory molecules and cytokines influence generation of T regulatory cells. Interactions of these molecules are closely related. In this paper we would like to pay attention to the importance of antigen presenting cells costimulatory potency in immune regulation during a pre-implantation period of pregnancy.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Antígenos CD/imunologia , Desenvolvimento Embrionário/imunologia , Tolerância Imunológica/imunologia , Gravidez/imunologia , Comunicação Celular/imunologia , Citocinas/imunologia , Células Dendríticas/imunologia , Feminino , Hormônios/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Interleucina-2 , Linfócitos/imunologia , Receptor Cross-Talk/imunologia , Sêmen/imunologia , Transdução de Sinais/imunologiaRESUMO
The role of the long noncoding RNA CCAT1 NC_000008.10:g.128220661C > T (rs67085638) in the development of colon cancer has been reported. Therefore, we assessed the prevalence of rs67085638 in patients with gastric cancer (GC). We also evaluated the effect of rs67085638 on B-cell-specific Moloney leukaemia virus insertion site 1 (BMI1) transcripts in primary GC and counterpart histopathologically confirmed disease-free margin tissue. Using high-resolution melting analysis, we evaluated rs67085638 frequency in patients with the GC genotype (n = 214) and controls (n = 502) in a Polish Caucasian population. qRT-PCR was used to determine BMI1 transcripts. We observed the trend of rs67085638 association in all patients with GC (ptrend = 0.028), a strong risk of the GC genotype in male (ptrend = 0.035) but not female (ptrend = 0.747) patients, and the association with non-cardia GC (ptrend = 0.041), tumour stages T3 (ptrend = 0.014) and T4 (ptrend = 0.032), differentiation grading G3 (ptrend = 0.009), lymph node metastasis stage N3 (ptrend = 0.0005) and metastasis stage M0 (ptrend = 0.027). We found that significantly increased BMI1 transcripts were associated with the primary GC genotype classified as grade G3 (p = 0.011) and as lymph node metastasis N3 (p = 0.010) and counterpart marginal tissues (p = 0.026, p = 0.040, respectively) from carriers of the T/T versus C/C genotypes. rs67085638 may contribute to increased BMI1 transcripts and the progression and rapid growth of GC.
Assuntos
Predisposição Genética para Doença , Complexo Repressor Polycomb 1/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Adulto , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genótipo , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Gástricas/patologiaRESUMO
Macrophages are antigen-presenting cells that have a key role in the regulation of immune phenomena and are responsible for the recognition of paternal antigens during pregnancy. The aim of this study was to investigate changes in the estrogen receptor alpha (ERalpha) protein level in splenic and uterine mature (F4/80(+)MHC II(+)) and immature (F4/80(+)MHC II(-) ) macrophages in female mice during time corresponding to the preimplantation period. C57BL/6J females in estrus were mated with Balb/c male mice or were mechanically stimulated through the vagina to achieve pseudopregnancy. Uterine and spleen cells were isolated on days 0.5 and 3.5 after mating or after uterine cervix stimulation. ERalpha content in macrophages was measured by flow cytometry and expressed as mean fluorescence intensity (MFI). The ERalpha level in splenic macrophages on 0.5 day after mating was higher than that in splenic macrophages of pseudopregnant mice on 0.5 day after stimulation. The ERalpha level was also higher in mature than in immature macrophages present in both the spleen and uterus, especially in mated mice. In the spleen, a correlation was found between the percentage of mature macrophages and ERalpha level in these cells. In conclusion, the elevated alpha level observed shortly after mating in splenic but not in uterine macrophages indicates an early systemic response to male antigens.
Assuntos
Receptor alfa de Estrogênio/metabolismo , Macrófagos/citologia , Prenhez/imunologia , Pseudogravidez/imunologia , Baço/metabolismo , Útero/citologia , Animais , Antígenos/imunologia , Antígenos/metabolismo , Copulação/fisiologia , Receptor alfa de Estrogênio/imunologia , Feminino , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Gravidez , Pseudogravidez/metabolismo , Sêmen/imunologia , Sêmen/metabolismo , Baço/imunologia , Útero/imunologiaRESUMO
Paramount to the efficacy of immune checkpoint inhibitors is proper selection of patients with adequate tumor immunogenicity and a robust but suppressed immune infiltrate. In colon cancer, immune-based therapies are approved for patients with DNA mismatch repair (MMR) deficiencies, in whom accumulation of genetic mutations results in increased neoantigen expression, triggering an immune response that is suppressed by the PD-L1/PD-1 pathway. Here, we report that characterization of the microenvironment of MMR-deficient metastatic colorectal cancer using multiplex fluorescent immunohistochemistry (mfIHC) identified increased infiltration of cytotoxic T lymphocytes (CTLs), which were more often engaged with epithelial cells (ECs) and improved overall survival. A subset of patients with intact MMR but a similar immune microenvironment to MMR-deficient patients was identified and found to universally express high levels of PD-L1, suggesting that they may represent a currently untreated, checkpoint inhibitor-responsive population. Further, PD-L1 expression on antigen-presenting cells (APCs) in the tumor microenvironment (TME) resulted in impaired CTL/EC engagement and enhanced infiltration and engagement of Tregs. Characterization of the TME by mfIHC highlights the interconnection between immunity and immunosuppression in metastatic colon cancer and may better stratify patients for receipt of immunotherapies.
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Neoplasias do Colo/imunologia , Neoplasias Hepáticas/secundário , Antígeno B7-H1/metabolismo , Sobreviventes de Câncer , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Reparo de Erro de Pareamento de DNA , Humanos , Imuno-Histoquímica , Imunofenotipagem , Repetições de Microssatélites , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Microambiente TumoralRESUMO
CD28H is a newly discovered co-receptor of the human B7 family. CD28H interacts with its ligand B7-H5 and regulates T cell response. Here we showed that CD28H was not expressed on granulocytes, monocytes, myeloid dendritic cells (MDCs), and B cells, but constitutively expressed with moderate levels on memory T cells and with high levels on naïve T cells, innate lymphoid cells (ILCs), natural killer (NK) cells, and plasmacytoid dendritic cells (PDCs) in human peripheral blood. Similar CD28H+ cell profile existed in secondary lymphoid organs and pathological tissues including multiple types of cancers. Further analysis demonstrated that CD28H+ naïve and CD28H+ memory T cells were characterized with increased naïve feature and less effector functional phenotype, respectively. High levels of constitutive CD28H expression on naïve T cells and innate immune cells suggest a potential role of CD28H in innate and adaptive immunity.
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Naïve T cells are poorly studied in cancer patients. We report that naïve T cells are prone to undergo apoptosis due to a selective loss of FAK family-interacting protein of 200 kDa (FIP200) in ovarian cancer patients and tumor-bearing mice. This results in poor antitumor immunity via autophagy deficiency, mitochondria overactivation, and high reactive oxygen species production in T cells. Mechanistically, loss of FIP200 disables the balance between proapoptotic and antiapoptotic Bcl-2 family members via enhanced argonaute 2 (Ago2) degradation, reduced Ago2 and microRNA1198-5p complex formation, less microRNA1198-5p maturation, and consequently abolished microRNA1198-5p-mediated repression on apoptotic gene Bak1 Bcl-2 overexpression and mitochondria complex I inhibition rescue T cell apoptosis and promoted tumor immunity. Tumor-derived lactate translationally inhibits FIP200 expression by down-regulating the nicotinamide adenine dinucleotide level while potentially up-regulating the inhibitory effect of adenylate-uridylate-rich elements within the 3' untranslated region of Fip200 mRNA. Thus, tumors metabolically target naïve T cells to evade immunity.
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Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Ácido Láctico/farmacologia , Neoplasias Ovarianas/metabolismo , Proteínas Tirosina Quinases/metabolismo , Linfócitos T/efeitos dos fármacos , Animais , Apoptose/genética , Autofagia/genética , Proteínas Relacionadas à Autofagia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ácido Láctico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Proteínas Tirosina Quinases/genética , Linfócitos T/metabolismoRESUMO
A recently paper published in Cell reports that dendritic cells (DCs) are dysfunctional in the tumor environment. Tumor impairs DC function through induction of endoplasmic reticulum stress response and subsequent disruption of lipid metabolic homeostasis.
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Proteínas de Ligação a DNA/metabolismo , Células Dendríticas/patologia , Estresse do Retículo Endoplasmático , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Fatores de Transcrição/metabolismo , Animais , Feminino , HumanosRESUMO
Myeloid-derived suppressor cells (MDSC) promote tumor growth by inhibiting T-cell immunity and promoting malignant cell proliferation and migration. The therapeutic potential of blocking MDSC in tumors has been limited by their heterogeneity, plasticity, and resistance to various chemotherapy agents. Recent studies have highlighted the role of energy metabolic pathways in the differentiation and function of immune cells; however, the metabolic characteristics regulating MDSC remain unclear. We aimed to determine the energy metabolic pathway(s) used by MDSC, establish its impact on their immunosuppressive function, and test whether its inhibition blocks MDSC and enhances antitumor therapies. Using several murine tumor models, we found that tumor-infiltrating MDSC (T-MDSC) increased fatty acid uptake and activated fatty acid oxidation (FAO). This was accompanied by an increased mitochondrial mass, upregulation of key FAO enzymes, and increased oxygen consumption rate. Pharmacologic inhibition of FAO blocked immune inhibitory pathways and functions in T-MDSC and decreased their production of inhibitory cytokines. FAO inhibition alone significantly delayed tumor growth in a T-cell-dependent manner and enhanced the antitumor effect of adoptive T-cell therapy. Furthermore, FAO inhibition combined with low-dose chemotherapy completely inhibited T-MDSC immunosuppressive effects and induced a significant antitumor effect. Interestingly, a similar increase in fatty acid uptake and expression of FAO-related enzymes was found in human MDSC in peripheral blood and tumors. These results support the possibility of testing FAO inhibition as a novel approach to block MDSC and enhance various cancer therapies.
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Neoplasias do Colo/terapia , Ácidos Graxos/metabolismo , Neoplasias Pulmonares/terapia , Linfócitos do Interstício Tumoral/imunologia , Células Mieloides/imunologia , Animais , Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Terapia Combinada , Avaliação Pré-Clínica de Medicamentos/métodos , Metabolismo Energético/imunologia , Compostos de Epóxi/uso terapêutico , Feminino , Humanos , Tolerância Imunológica/imunologia , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos C57BL , Oxirredução/efeitos dos fármacos , Microambiente Tumoral/imunologiaAssuntos
Interferon gama/metabolismo , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T/metabolismo , Animais , Antígeno B7-H1/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Antígenos de Histocompatibilidade Classe I , Humanos , Linfonodos , Masculino , Camundongos , Camundongos Knockout , Fenótipo , TimoRESUMO
PROBLEM: The object of the study was to investigate the costimulatory phenotype of spleen antigen-presenting cells (APCs) in mice after mating and the influence of costimulatory signal blocking on pregnancy outcome, cytokine production, and Treg cell concentration. METHOD OF STUDY: The levels of CD40, CD80, and CD86 on spleen APCs at day 0.5 and 3.5 after mating (C57BL/6Jx DBA/2J and C57BL/6JxBalb/c) were assessed by flow cytometry and RT-PCR. Blocking antibodies against costimulatory molecules were given i.p. at day 3.5 after mating. Pregnancy outcomes, blood cytokine (ELISA), and spleen Treg (flow cytometry) concentrations were examined at day 10.5 after mating. RESULTS: Differential expression of costimulatory molecules on spleen APCs of mated v. pseudopregnant mice was observed mainly at day 3.5 after conception. Administration of anti-CD86 antibody lowered pregnancy outcome. Cytokine expression was modulated after administration of anti-CD86, anti-CD80 and anti-CD40 antibodies, whereas only anti-CD40 antibody changed the concentration of Treg lymphocytes and the level of Foxp3 protein expression. CONCLUSION: Costimulatory phenotype of female spleen APCs is distinctly modulated after mating. Alteration of costimulatory signal derived from APCs during pre-implantation period of pregnancy may have an adverse effect on pregnancy outcome and the tolerogenic immune response.