RESUMO
Ferroptosis is a novel form of cell death characterized by heavy iron accumulation and lipid peroxidation that plays a critical role in the tumor microenvironment. However, promising biomarkers associated with tumor immune cell infiltration and the immunotherapy response to ferroptosis regulators remain to be elucidated in lung adenocarcinoma (LUAD) patients. In this study, we defined ferroptosis regulators in LUAD through database analysis and experimental validation to determine the implementation of genes associated with clinical relevance, immunotherapy response and tumor microenvironment in LUAD patients. Multiomics data analysis was performed to explore the CNV features, molecular mechanisms and immunogenic characteristics of ferroptosis regulators in LUAD patients. Then, univariate and multivariate Cox regression analyses were used to identify three genes (DDIT4, RRM2, and SLC2A1) that were closely associated with the prognosis of LUAD patients. The prognostic model based on the determination of these three genes was an independent prognostic factor (p < 0.05, HR = 2.838), and patients with superior predictive performance and higher prognostic risk were more likely to have poor survival rates than those with lower prognostic risk in the training group (p < 0.001, HR = 3.19) and the test group (p < 0.001, HR = 2.94; p < 0.001, HR = 3.44). Activated immune cells, including T helper cells and activated CD8 T cells, were lower in the high-risk group, while type 2 T cells were higher (p < 0.05). Patients with higher prognostic risk were less likely to benefit from immunotherapy, partly due to low CTLA4 levels and an immunosuppressive microenvironment (p < 0.05). Combined with LUAD tissue samples and mouse trials, RRM2 was found to influence lung cancer progression and affect tumor immune cell infiltration. RRM2 inhibition effectively promoted M1 macrophage polarization and suppressed M2 macrophage polarization in vitro and in vivo. And ferroptosis inhibitor ferrostatin-1 treatment effectively re-blanced macrophage polarization mediated by RRM2 inhibition. Taken together, the results of the multiomics data analysis and experimental validation identified ferroptosis regulators as promising biomarkers and therapeutic targets associated with tumor immune infiltration in LUAD patients.
Assuntos
Adenocarcinoma de Pulmão/imunologia , Biomarcadores Tumorais/metabolismo , Ferroptose/fisiologia , Neoplasias Pulmonares/imunologia , Ribonucleosídeo Difosfato Redutase/metabolismo , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Animais , Biomarcadores Tumorais/imunologia , Xenoenxertos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologiaRESUMO
Tumor-associated thrombus (TAT) accounts for a high proportion of venous thromboembolism. Traditional thrombolysis and anticoagulation methods are not effective due to various complications and contraindications, which can easily lead to patients dying from TAT rather than the tumor itself. These clinical issues demonstrate the need to research diverse pathways for adjuvant thrombolysis in antitumor therapy. Previously, the phenotypic and functional transformation of monocytes/macrophages is widely reported to be involved in intratribal collagen regulation. This study finds that myeloid deficiency of the oncogene SHP2 sensitizes Ly6Clow monocyte/macrophage differentiation and can alleviate thrombus organization by increasing thrombolytic Matrix metalloproteinase (MMP) 2/9 activities. Moreover, pharmacologic inhibition by SHP099, examined in mouse lung metastatic tumor models, reduces tumor and thrombi burden in tumor metastatic lung tissues. Furthermore, SHP099 increases intrathrombus Ly6Clow monocyte/macrophage infiltration and exhibits thrombolytic function at high concentrations. To improve the thrombolytic effect of SHP099, NanoSHP099 is constructed to achieve the specific delivery of SHP099. NanoSHP099 is identified to be simultaneously enriched in tumor and thrombus foci, exerting dual tumor-suppression and thrombolysis effects. NanoSHP099 presents a superior thrombus dissolution effect than that of the same dosage of SHP099 because of the higher Ly6Clow monocyte/macrophage proportion and MMP2/MMP9 collagenolytic activities in organized thrombi.
Assuntos
Monócitos , Trombose , Animais , Camundongos , Leucócitos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Monócitos/efeitos dos fármacos , Terapia Trombolítica/métodos , Trombose/metabolismo , Piperidinas/farmacologia , Pirimidinas/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidoresRESUMO
Tumor-associated macrophages (TAMs) play an important role in remodeling the tumor microenvironment (TME), which promotes tumor growth, immunosuppression and angiogenesis. Because of the high plasticity of macrophages and the extremely complex tumor microenvironment, the mechanism of TAMs in cancer progression is still largely unknown. In this study, we found that xCT (SLC7A11) was overexpressed in lung cancer-associated macrophages. Higher xCT in TAMs was associated with poor prognosis and was an independent predictive factor in lung cancer. In addition, lung cancer growth and progression was inhibited in xCT knockout mice, especially macrophage-specific xCT knockout mice. We also found that the deletion of macrophage xCT inhibited AKT/STAT6 signaling activation and reduced M2-type polarization of TAMs. Macrophage xCT deletion recruited more CD8+ T cells and activated the lung cancer cell-mediated and IFN-γ-induced JAK/STAT1 axis and increased the expression of its target genes, including CXCL10 and CD274. The combination of macrophage xCT deletion and anti-PDL1 antibody achieved better tumor inhibition. Finally, combining the xCT inhibitor erastin with an anti-PDL1 antibody was more potent in inhibiting lung cancer progression. Therefore, suppression of xCT may overcome resistance to cancer immunotherapy.
Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Animais , Camundongos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Macrófagos/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos Knockout , Microambiente Tumoral , Ativação de MacrófagosRESUMO
SIPRα on macrophages binds with CD47 to resist proengulfment signals, but how the downstream signal of SIPRα controls tumor-infiltrating macrophages (TIMs) is still poorly clarified. Here, we report that the CD47/signal regulatory protein α (SIRPα) axis requires the deneddylation of tyrosine phosphatase SHP2. Mechanistically, Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) was constitutively neddylated on K358 and K364 sites; thus, its autoinhibited conformation was maintained. In response to CD47-liganded SIRPα, SHP2 was deneddylated by sentrin-specific protease 8 (SENP8), which led to the dephosphorylation of relevant substrates at the phagocytic cup and subsequent inhibition of macrophage phagocytosis. Furthermore, neddylation inactivated myeloid-SHP2 and greatly boosted the efficacy of colorectal cancer (CRC) immunotherapy. Importantly, we observed that supplementation with SHP2 allosteric inhibitors sensitized immune treatment-resistant CRC to immunotherapy. Our results emphasize that the CRC subtype that is unresponsive to immunotherapy relies on SIRPαhiSHP2hiNEDD8lo TIMs and highlight the need to further explore the strategy of SHP2 targeting in CRC therapy.
Assuntos
Antígeno CD47 , Neoplasias do Colo , Humanos , Antígenos de Diferenciação/genética , Antígeno CD47/genética , Antígeno CD47/metabolismo , Neoplasias do Colo/genética , Endopeptidases , Terapia de Imunossupressão , Imunoterapia/métodos , Fagocitose , Receptores ImunológicosRESUMO
Oxidative stress contributes to the pathogenesis of acute lung injury. Protein S-glutathionylation plays an important role in cellular antioxidant defense. Here we report that the expression of deglutathionylation enzyme Grx1 is decreased in the lungs of acute lung injury mice. The acute lung injury induced by hyperoxia or LPS is significantly relieved in Grx1 KO and Grx1fl/flLysMcre mice, confirming the protective role of Grx1-regulated S-glutathionylation in macrophages. Using a quantitative redox proteomics approach, we show that FABP5 is susceptible to S-glutathionylation under oxidative conditions. S-glutathionylation of Cys127 in FABP5 promotes its fatty acid binding ability and nuclear translocation. Further results indicate S-glutathionylation promotes the interaction of FABP5 and PPARß/δ, activates PPARß/δ target genes and suppresses the LPS-induced inflammation in macrophages. Our study reveals a molecular mechanism through which FABP5 S-glutathionylation regulates macrophage inflammation in the pathogenesis of acute lung injury.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Proteínas de Ligação a Ácido Graxo/metabolismo , Inflamação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estresse Oxidativo , Substâncias Protetoras/farmacologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Proteínas de Ligação a Ácido Graxo/genética , Regulação da Expressão Gênica , Glutarredoxinas/genética , Glutarredoxinas/metabolismo , Hiperóxia , Pulmão/patologia , Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredução , Processamento de Proteína Pós-Traducional , Proteínas RecombinantesRESUMO
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing unremitting extracellular matrix deposition. Transforming growth factor-ß (TGF-ß) superfamily involves bone morphogenetic proteins (BMPs) and TGF-ß, and the balance between the activation of TGF-ß-dependent SMADs (Smad2/3) and BMP-dependent SMADs (Smad1/5/8) is essential for fibrosis process. GREM2, initially identified as a TGF-ß-inducible gene, encodes a small secreted glycoprotein belonging to a group of matricellular proteins, its role in lung fibrosis is not clear. Here, we identified Gremlin2 as a key regulator of fibroblast activation. Gremlin2 was highly expressed in the serum and lung tissues in IPF patients. Bleomycin-induced lung fibrosis model exhibited high expression of Gremlin2 in the bronchoalveolar lavage fluid (BALF) and lung tissue. Isolation of primary cells from bleomycin-induced fibrosis lung showed a good correlation of Gremlin2 and Acta2 (α-SMA) expressions. Overexpression of Gremlin2 in human fetal lung fibroblast 1 (HFL-1) cells increased its invasion and migration. Furthermore, Gremlin2 regulates fibrosis functions through mediating TGF-ß/BMP signaling, in which Gremlin2 may activate TGF-ß signaling and inhibit BMP signaling. Therefore, we provided in vivo and in vitro evidence to demonstrate that Gremlin2 may be a potential therapeutic target for the treatment of IPF.