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1.
Biomaterials ; 313: 122766, 2025 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-39180916

RESUMO

The immune resistance of tumor microenvironment (TME) causes immune checkpoint blockade therapy inefficient to hepatocellular carcinoma (HCC). Emerging strategies of using chemotherapy regimens to reverse the immune resistance provide the promise for promoting the efficiency of immune checkpoint inhibitors. The induction of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) in tumor cells evokes the adaptive immunity and remodels the immunosuppressive TME. In this study, we report that mitoxantrone (MIT, a chemotherapeutic drug) activates the cGAS-STING signaling pathway of HCC cells. We provide an approach to augment the efficacy of MIT using a signal transducer and activator of transcription 3 (STAT3) inhibitor called napabucasin (NAP). We prepare an aminoethyl anisamide (AEAA)-targeted polyethylene glycol (PEG)-modified poly (lactic-co-glycolic acid) (PLGA)-based nanocarrier for co-delivery of MIT and NAP. The resultant co-nanoformulation can elicit the cGAS-STING-based immune responses to reshape the immunoresistant TME in the mice orthotopically grafted with HCC. Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy.


Assuntos
Carcinoma Hepatocelular , Imunoterapia , Neoplasias Hepáticas , Proteínas de Membrana , Mitoxantrona , Nucleotidiltransferases , Fator de Transcrição STAT3 , Mitoxantrona/farmacologia , Mitoxantrona/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Animais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Humanos , Nucleotidiltransferases/metabolismo , Proteínas de Membrana/metabolismo , Fator de Transcrição STAT3/metabolismo , Camundongos , Imunoterapia/métodos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Benzofuranos , Naftoquinonas
2.
World J Gastrointest Oncol ; 16(9): 3875-3886, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39350978

RESUMO

BACKGROUND: Inflammation-related markers including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI) and prognostic nutritional index (PNI) could reflect tumor immune microenvironment and predict prognosis of cancers. However, it had not been explored in alpha-fetoprotein (AFP) producing gastric cancer (GC). AIM: To determine the predictive value of inflammation-related peripheral blood markers including as NLR, PLR, MLR, SII, SIRI and PNI in the prognosis of AFP- producing GC (AFPGC). Besides, this study would also compare the differences in tumor immune microenvironment, clinical characteristics and prognosis between AFPGC and AFP- GC patients to improve the understanding of this disease. METHODS: 573 patients enrolled were retrospectively studied. They were divided into AFP+ group (AFP ≥ 20 ng/mL) and AFP- group (AFP < 20 ng/mL), comparing the levels of NLR/PLR/MLR/SII/SIRI/PNI and prognosis. In AFP+ group, the impact of NLR/PLR/MLR/SII/SIRI/PNI and their dynamic changes on prognosis were further explored. RESULTS: Compared with AFP- patients, AFP+ patients had higher NLR/PLR/MLR/SII/SIRI and lower PNI levels and poorer overall survival (OS). In the AFP+ group, mortality was significantly lower in the lower NLR/PLR/MLR/SII/SIRI group and higher PNI group. Moreover, the dynamic increase (NLR/PLR/MLR/SII/SIRI) or decrease (PNI) was associated with the rise of mortality within 1 year of follow-up. CONCLUSION: Compared with AFP- patients, the level of inflammation-related peripheral blood markers significantly increased in AFP+ patients, which was correlated with OS of AFP+ patients. Also, the gradual increase of SII and SIRI was associated with the risk of death within one year in AFP+ patients. AFPGC should be considered as a separate type and distinguished from AFP- GC because of the difference in tumor immune microenvironment. It requires basic experiments and large clinical samples in the future.

3.
J Egypt Natl Canc Inst ; 36(1): 30, 2024 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-39370456

RESUMO

BACKGROUND: Although advances in immune checkpoint inhibitor (ICI) research have provided a new treatment approach for lung adenocarcinoma (LUAD) patients, their survival is still unsatisfactory, and there are issues in the era of response prediction to immunotherapy. METHODS: Using bioinformatics methods, a prognostic signature was constructed, and its predictive ability was validated both in the internal and external datasets (GSE68465). We also explored the tumor-infiltrating immune cells, mutation profiles, and immunophenoscore (IPS) in the low-and high-risk groups. RESULTS: As far as we are aware, this is the first study which introduces a novel prognostic signature model using BIRC5, CBLC, S100P, SHC3, ANOS1, VIPR1, LGR4, PGC, and IGKV4.1. According to multivariate analysis, the 9-immune-related genes (IRGs) signature provided an independent prognostic factor for the overall survival (OS). The low-risk group had better OS, and the tumor mutation burden (TMB) was significantly lower in this group. Moreover, the risk scores were negatively associated with the tumor-infiltrating immune cells, like CD8+ T cells, macrophages, dendritic cells, and NK cells. In addition, the IPS were significantly higher in the low-risk group as they had higher gene expression of immune checkpoints, suggesting that ICIs could be a promising treatment option for low-risk LUAD patients. CONCLUSION: The combination of these 9-IRGs not only could efficiently predict overall survival of LUAD patients but also show a powerful association with the expression of immune checkpoints and response to ICIs based on IPS; hoping this model paves the way for better stratification and management of patients in clinical practice.


Assuntos
Adenocarcinoma de Pulmão , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Prognóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Feminino , Biomarcadores Tumorais/genética , Pessoa de Meia-Idade , Linfócitos do Interstício Tumoral/imunologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Idoso , Transcriptoma , Mutação , Biologia Computacional/métodos
4.
Cancers (Basel) ; 16(20)2024 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-39456562

RESUMO

Breast cancer remains one of the leading causes of death among women worldwide, and recent research highlights its growing connection to alterations in the microbiota. This review delves into the intricate relationship between microbiotas and breast cancer, exploring its presence in healthy breast tissue, its changes during cancer progression, and its considerable impact on both the tumor microenvironment (TME) and the tumor immune microenvironment (TIME). We extensively analyze how the microbiota influences cancer growth, invasion, metastasis, resistance to drugs, and the evasion of the immune system, with a special focus on its effects on the TIME. Furthermore, we investigate distinct microbial profiles associated with the four primary molecular subtypes of breast cancer, examining how the microbiota in tumor tissues compares with that in adjacent normal tissues. Emerging studies suggest that microbiotas could serve as valuable diagnostic and prognostic biomarkers, as well as targets for therapy. This review emphasizes the urgent need for further research to improve strategies for breast cancer prevention, diagnosis, and treatment. By offering a detailed examination of the microbiota's critical role in breast cancer, this review aims to foster the development of novel microbiota-based approaches for managing the disease.

5.
Clin Transl Oncol ; 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39412635

RESUMO

BACKGROUND: The metabolic environment of glioma is extremely complex. Pyrimidine metabolism can significantly influence malignant progression of multiple kinds of cancer cells. In this study, we intend to explore the relationship between pyrimidine metabolism and malignant progression of glioma. METHODS: We analyzed two glioma RNA-sequencing databases to construct a pyrimidine metabolism-related risk signature. An individualized prognosis prediction model based on this risk signature was established. Functional analysis and in vitro experiments were conducted to assess the role of pyrimidine metabolism in the tumor-immune microenvironment and malignant progress of gliomas. RESULTS: The high-risk group, as predicted by the pyrimidine metabolism-related risk score, showed a tendency toward more malignant entities and poorer survival outcomes. Functional analysis revealed that pyrimidine metabolism significantly regulates the tumor-immune microenvironment. In vitro experiments confirmed that targeting pyrimidine metabolism-related genes can inhibit malignancy of glioma cell. CONCLUSION: In short, the pyrimidine metabolism-related signature we established could serve as an independent prognostic biomarker in diffuse gliomas and has a close association with regulation of the tumor-immune microenvironment.

6.
Front Immunol ; 15: 1467858, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39445005

RESUMO

Introduction: Low-grade gliomas (LGG) represent a heterogeneous and complex group of brain tumors. Despite significant progress in understanding and managing these tumors, there are still many challenges that need to be addressed. Glycosylation, a common post-translational modification of proteins, plays a significant role in tumor transformation. Numerous studies have demonstrated a close relationship between glycosylation modifications and tumor progression. However, the biological function of glycosylation-related genes in LGG remains largely unexplored. Their potential roles within the LGG microenvironment are also not well understood. Methods: We collected RNA-seq data and scRNA-seq data from patients with LGG from TCGA and GEO databases. The glycosylation pathway activity scores of each cluster and each patient were calculated by irGSEA and GSVA algorithms, and the differential genes between the high and low glycosylation pathway activity score groups were identified. Prognostic risk profiles of glycosylation-related genes were constructed using univariate Cox and LASSO regression analyses and validated in the CGGA database. Results: An 8 genes risk score signature including ASPM, CHI3L1, LILRA4, MSN, OCIAD2, PTGER4, SERPING1 and TNFRSF12A was constructed based on the analysis of glycosylation-related genes. Patients with LGG were divided into high risk and low risk groups according to the median risk score. Significant differences in immunological characteristics, TIDE scores, drug sensitivity, and immunotherapy response were observed between these groups. Additionally, survival analysis of clinical medication information in the TCGA cohort indicated that high risk and low risk groups have different sensitivities to drug therapy. The risk score characteristics can thus guide clinical medication decisions for LGG patients. Conclusion: Our study established glycosylation-related gene risk score signatures, providing new perspectives and approaches for prognostic prediction and treatment of LGG.


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Glicosilação , Glioma/genética , Glioma/terapia , Glioma/mortalidade , Prognóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Biomarcadores Tumorais/genética , Gradação de Tumores , Regulação Neoplásica da Expressão Gênica , Feminino , Masculino , Microambiente Tumoral/genética , Perfilação da Expressão Gênica , Medição de Risco , Bases de Dados Genéticas
7.
Med Oncol ; 41(12): 300, 2024 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-39453562

RESUMO

Hepatocellular carcinoma (HCC) ranks among the most prevalent types of cancer in the world and its incidence and mortality are increasing year by year, frequently diagnosed at an advanced stage. Traditional treatments such as surgery, chemotherapy, and radiotherapy have limited efficacy, so new diagnostic and treatment strategies are urgently needed. Recent research has discovered that intratumoral microbiota significantly influences the development, progression, and metastasis of HCC by modulating inflammation, immune responses, and cellular signaling pathways. Intratumoral microbiota contributes to the pathologic process of HCC by influencing the tumor microenvironment and altering the function of immune system. This article reviews the mechanism of intratumoral microbiota in HCC and anticipates the future possibilities of intratumoral microbiota-based therapeutic strategies for HCC management. This emerging field provides fresh insights into early diagnosis and personalized approaches for HCC while holding substantial clinical application potential to improve patient outcomes and tailor interventions to individual tumor profiles.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Microbiota , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Microambiente Tumoral
8.
ACS Appl Mater Interfaces ; 16(42): 56634-56652, 2024 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-39378273

RESUMO

Lung cancer has emerged as the second most common type of malignant tumor worldwide, and it has the highest mortality rate. The overall 5-year survival rate stands at less than 20%, which is primarily related to the limited therapeutic options and the complexity of the tumor immune microenvironment. In the tumor microenvironment, M1 macrophages are known for their tumor-killing capabilities. Although they are less numerous, they play an important role in tumor immunity. Therefore, increasing M1 macrophages' presence is considered a strategy to enhance targeted phagocytosis and antitumor efficacy in nonsmall cell lung cancer (NSCLC). This study introduces the development of folic acid (FA)-conjugated liposomal nanobubbles for precise delivery of PFH, STAT3 siRNA, and Fe3O4 to the tumor microenvironment. These encapsulated PFH liposomal nanobubbles exhibit significant visualization potential and underwent phase transition when exposed to low-intensity focused ultrasound (LIFU). The release of Fe3O4 activates the IRF5 signaling pathway, converting M2-like macrophages to M1. In addition, STAT3 siRNA effectively interrupts the JAK-STAT3 pathway, inhibiting the polarization of M2-like macrophages in tumor-associated macrophages (TAMs). This dual-action therapy facilitates T-cell activation and proliferation, thereby enhancing the immune response against NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Macrófagos , RNA Interferente Pequeno , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , RNA Interferente Pequeno/química , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Animais , Camundongos , Humanos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Lipossomos/química , Ácido Fólico/química , Nanopartículas de Magnetita/química , Microambiente Tumoral/efeitos dos fármacos , Ondas Ultrassônicas , Portadores de Fármacos/química
9.
ACS Nano ; 2024 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-39441690

RESUMO

Hypoxia, a common occurrence within solid tumors, can stimulate the dissemination of deceptive tumor exosomes, which function as communicative bridges and orchestrate the recruitment of various supportive cell types for enhanced tumor adaptability in a tumor immune microenvironment. Current nanotechnology provides us intelligent strategies to combat the hypoxic tumor microenvironment. However, once exposed to external stimuli, such as chemotherapy, tumor cells simultaneously release malignant signals to develop tumor migration and immunosuppression, posing challenges to clinical practice. Taking advantage of the membrane-targeting therapeutic strategy, the application of a self-assembled short peptide (PepABS-py), affording hydrogels on tumor cell surfaces, can block exosome dissemination with fiber-like nanostructures and effectively limit the systemic adverse effects of traditional therapeutics. Moreover, PepABS-py can attenuate the hypoxic tumor microenvironment in vivo by carrying an inhibitor of the hypoxic tumor-overexpressed CA IX enzyme, where hypoxia is also a crucial regulator to induce tumor exosomes and mediate intercellular communications within the immune system. Herein, its application on jamming exosome communications can target the T cell-related signaling pathway by regulating microRNAs in exosome cargoes and ultimately enhances CD8+ T cell infiltration and alleviates inflammatory monocytes at metastasis sites. Collectively, with the capability of blocking exosome dissemination, PepABS-py can be applied as a promising tumor membrane-targeting therapeutic tool to counter tumor adaption within an immune microenvironment and further advance traditional chemotherapy.

10.
J Ovarian Res ; 17(1): 207, 2024 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-39427186

RESUMO

The MECOM locus is a gene frequently amplified in high-grade serous ovarian carcinoma (HGSOC). Nevertheless, the body of research examining the associations among MECOM transcripts, patient prognosis, and their role in modulating the tumor immune microenvironment (TIME) remains sparse, particularly in large cohorts. This study assessed the expression of MECOM transcripts in 352 HGSOC patients and 88 normal ovarian tissues from the combined GTEx/TCGA database. Using resources such as the UCSC Genome Browser, Ensembl, and NextProt, two transcripts corresponding to classical protein isoforms from MECOM were identified. Cox proportional hazards regression analysis, Kaplan-Meier survival curves, and a comprehensive TIME evaluation algorithm were employed to elucidate the connections between the expression levels of these transcripts and both patient prognosis and TIME status. Chromatin Immunoprecipitation sequencing (ChIP-seq) data for the two protein isoforms, as well as RNA sequencing data post-targeted silencing, were analyzed to identify potential regulatory targets of the different transcription factors. Elevated expression of the MECOM isoform transcripts was correlated with poorer survival in HGSOC patients, potentially through the modulation of cancer-associated fibroblasts (CAFs) and immunosuppressive cell populations. In contrast, higher levels of EVI1 isoform transcripts were linked to enhanced survival, possibly due to the regulation of CD8+ T cells, macrophages, and a reduction in the expression of JUN protein, or its DNA-binding activity on downstream genes. Diverse protein isoforms derived from MECOM were found to differentially affect the survival and tumor development in ovarian cancer patients through specific mechanisms. Investigating the molecular mechanisms underlying disease pathogenesis and identifying potential drug target proteins at the level of splice variant isoforms were deemed crucial.


Assuntos
Neoplasias Ovarianas , Isoformas de Proteínas , Microambiente Tumoral , Humanos , Feminino , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Isoformas de Proteínas/genética , Prognóstico , Regulação Neoplásica da Expressão Gênica
11.
Cureus ; 16(9): e69790, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39429383

RESUMO

Background Oral squamous cell carcinoma (OSCC) accounts for the majority of oral cancers globally. It is characterized by metastasis, poor prognosis, high recurrence rate, and poor five-year survival rate due to late detection or diagnosis at an advanced stage. Novel biomarkers that can predict the prognosis of patients with OSCC are needed to improve survival. Lysosome-associated membrane protein-3 (LAMP3) glycoprotein, a member of the LAMP protein family, is a molecular marker for mature dendritic cells. LAMP3 expression has been correlated with unfavorable prognosis in patients with various cancers. Few studies have examined the relationship between LAMP3 and clinicopathological parameters in OSCC. This study aims to analyze the immunohistochemical expression of LAMP3 in OSCC and its relationship with clinicopathological characteristics. Methodology In this study, 75 formalin-fixed, paraffin-embedded samples of cases diagnosed with primary OSCC were obtained and immunostained with LAMP3 antibody. Its expression was compared with clinicopathological parameters such as age, sex, tobacco and alcohol consumption habits, differentiation, TNM staging, tumor location, lymph node metastasis, lymphovascular invasion, perineural invasion, and pattern of invasion. Results Higher LAMP3 expression was highly significantly associated with the TNM stage (p = 0.001). High expression of LAMP3 was significantly associated with T stage (p = 0.002) and lymph node metastasis (p = 0.002). All poorly differentiated OSCC cases (n = 2, 100%) showed a high expression of LAMP3. Conclusions High LAMP3 expression and its significant association with TNM stage, T stage, and lymph node metastasis suggest a potential role for LAMP3 in OSCC carcinogenesis. High LAMP3 expression in poorly differentiated OSCC might indicate that it plays a pivotal role in oncogenic cell transformation. Our results indicate that LAMP3 may be a predictive marker for poor prognosis in OSCC.

12.
Transl Lung Cancer Res ; 13(9): 2395-2410, 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39430335

RESUMO

Background: Emerging evidence has underscored the crucial role of infiltrating immune cells in the tumor immune microenvironment (TIME) of non-small cell lung cancer (NSCLC) development and progression. With the implementation of screening programs, the incidence of early-stage NSCLC is rising. However, the high risk of recurrence and poor survival rates associated with this disease necessitate a deeper understanding of the TIME and its relationship with driver alterations. The aim of this study was to provide an in-depth analysis of immune changes in early-stage NSCLC, highlighting the significant transitions in immune response during disease progression. Methods: Tumor tissues were collected from 105 patients with precancerous lesions or stage I-III NSCLC. Next-generation sequencing (NGS) was used to detect cancer driver alterations. Multiplex immunofluorescence (mIF) was performed to evaluate immune cell density, percentage, and spatial proximity to cancer cells in the TIME. Next Among these patients, 64 had NGS results, including three with adenocarcinoma in situ (AIS), 10 with minimally invasive adenocarcinoma (MIA), and 51 with stage I invasive cancers. Additionally, three patients underwent neoadjuvant immuno-chemotherapy and tumor tissue specimens before and after treatment were obtained. Results: Patients with stage I invasive cancer had significantly higher density (P=0.01) and percentage (P=0.02) of CD8+ T cells and higher percentages of M1 macrophages (P=0.04) and immature natural killer (NK) cells (P=0.041) in the tumor parenchyma compared to those with AIS/MIA. Patients with mutated epidermal growth factor receptor (EGFR) gene exhibited decreased NK cell infiltration, increased M2 macrophage infiltration, and decreased aggregation of CD4+ T cells near tumor cells compared to EGFR wild-type patients. As NSCLC progressed from stage I to III, CD8+ T cell density and proportion increased, while PD-L1+ tumor cells were in closer proximity to PD-1+CD8+ T cells, potentially inhibiting CD8+ T cell function. Furthermore, M1 macrophages decreased in density and proportion, and the number of NK cells, macrophages, and B cells around tumor cells decreased. Additionally, patients with tertiary lymphoid structures (TLSs) had significantly higher proportion of M1 macrophages and lymphocytes near tumor cells, whereas those without TLS had PD-L1+ tumor cells more densely clustered around PD-1+CD8+ T cells. Notably, neoadjuvant immuno-chemotherapy induced the development of TLS. Conclusions: This study offers an in-depth analysis of immune changes in NSCLC, demonstrating that the transition from AIS/MIA to invasive stage I NSCLC leads to immune activation, while the advancement from stage I to stage III cancer results in immune suppression. These findings contribute to our understanding of the molecular mechanisms underlying early-stage NSCLC progression and pave the way for the identification of potential treatment options.

13.
Mol Genet Genomics ; 299(1): 100, 2024 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-39460829

RESUMO

Heterogeneous behavior of each cell type and their cross-talks in tumor immune microenvironment (TIME) refers to tumor immunological heterogeneity that emerges during tumor progression and represents formidable challenges for effective anti-tumor immune response and promotes drug resistance. To comprehensively elucidate the heterogeneous behavior of individual cell types and their interactions across different stages of tumor development at system level, a computational framework was devised that integrates cell specific data from single-cell RNASeq into networks illustrating interactions among signaling and metabolic response genes within and between cells in TIME. This study identified stage specific novel markers which remodel the cross-talks, thereby facilitating immune stimulation. Particularly, multicellular knockout of metabolic gene APOE (Apolipoprotein E in mast cell, myeloid cell and fibroblast) combined with signaling gene CAV1 (Caveolin1 in endothelial and epithelial cells) resulted in the activation of T-cell mediated signaling pathways. Additionally, this knockout also initiated intervention of cytotoxic gene regulations during tumor immune cell interactions at the early stage of Lung Adenocarcinoma (LUAD). Furthermore, a unique interaction motif from multiple cells emerged significant in regulating the overall immune response at the advanced stage of LUAD. Most significantly, FCER1G (Fc Fragment of IgE Receptor Ig) was identified as the common regulator in activating the anti-tumor immune response at both stages. Predicted markers exhibited significant association with patient overall survival in patient specific dataset. This study uncovers the significance of signaling and metabolic interplay within TIME and discovers important targets to enhance anti-tumor immune response at each stage of tumor development.


Assuntos
Adenocarcinoma de Pulmão , Comunicação Celular , Neoplasias Pulmonares , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Comunicação Celular/imunologia , Comunicação Celular/genética , Apolipoproteínas E/genética , Caveolina 1/genética , Caveolina 1/metabolismo , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais , Estadiamento de Neoplasias , Mastócitos/imunologia , Mastócitos/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo
14.
Proc Natl Acad Sci U S A ; 121(42): e2317694121, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39388266

RESUMO

Histone Deacetylase 3 (HDAC3) function in vivo is nuanced and directed in a tissue-specific fashion. The importance of HDAC3 in Kras mutant lung tumors has recently been identified, but HDAC3 function in this context remains to be fully elucidated. Here, we identified HDAC3 as a lung tumor cell-intrinsic transcriptional regulator of the tumor immune microenvironment. In Kras mutant lung cancer cells, we found that HDAC3 is a direct transcriptional repressor of a cassette of secreted chemokines, including Cxcl10. Genetic and pharmacological inhibition of HDAC3 robustly up-regulated this gene set in human and mouse Kras, LKB1 (KL) and Kras, p53 (KP) mutant lung cancer cells through an NF-κB/p65-dependent mechanism. Using genetically engineered mouse models, we found that HDAC3 inactivation in vivo induced expression of this gene set selectively in lung tumors and resulted in enhanced T cell recruitment at least in part via Cxcl10. Furthermore, we found that inhibition of HDAC3 in the presence of Kras pathway inhibitors dissociated Cxcl10 expression from that of immunosuppressive chemokines and that combination treatment of entinostat with trametinib enhanced T cell recruitment into lung tumors in vivo. Finally, we showed that T cells contribute to in vivo tumor growth control in the presence of entinostat and trametinib combination treatment. Together, our findings reveal that HDAC3 is a druggable endogenous repressor of T cell recruitment into Kras mutant lung tumors.


Assuntos
Quimiocina CXCL10 , Histona Desacetilases , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas p21(ras) , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Animais , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Humanos , Camundongos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Linhagem Celular Tumoral , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Mutação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Pirimidinonas/farmacologia , Piridonas/farmacologia , Microambiente Tumoral/imunologia , Transcrição Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Piridinas/farmacologia , Benzamidas
15.
Brief Bioinform ; 25(6)2024 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-39451158

RESUMO

Enhancing patient response to immune checkpoint inhibitors (ICIs) is crucial in cancer immunotherapy. We aim to create a data-driven mathematical model of the tumor immune microenvironment (TIME) and utilize deep reinforcement learning (DRL) to optimize patient-specific ICI therapy combined with chemotherapy (ICC). Using patients' genomic and transcriptomic data, we develop an ordinary differential equations (ODEs)-based TIME dynamic evolutionary model to characterize interactions among chemotherapy, ICIs, immune cells, and tumor cells. A DRL agent is trained to determine the personalized optimal ICC therapy. Numerical experiments with real-world data demonstrate that the proposed TIME model can predict ICI therapy response. The DRL-derived personalized ICC therapy outperforms predefined fixed schedules. For tumors with extremely low CD8 + T cell infiltration ('extremely cold tumors'), the DRL agent recommends high-dosage chemotherapy alone. For tumors with higher CD8 + T cell infiltration ('cold' and 'hot tumors'), an appropriate chemotherapy dosage induces CD8 + T cell proliferation, enhancing ICI therapy outcomes. Specifically, for 'hot tumors', chemotherapy and ICI are administered simultaneously, while for 'cold tumors', a mid-dosage of chemotherapy makes the TIME 'hotter' before ICI administration. However, in several 'cold tumors' with rapid resistant tumor cell growth, ICC eventually fails. This study highlights the potential of utilizing real-world clinical data and DRL algorithm to develop personalized optimal ICC by understanding the complex biological dynamics of a patient's TIME. Our ODE-based TIME dynamic evolutionary model offers a theoretical framework for determining the best use of ICI, and the proposed DRL agent may guide personalized ICC schedules.


Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Medicina de Precisão , Imunoterapia
16.
Cells ; 13(20)2024 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-39451239

RESUMO

Aging is an important risk factor for tumorigenesis. Metabolic reprogramming is a hallmark of both aging and tumor initiation. However, the manner in which the crosstalk between aging and metabolic reprogramming affects the tumor microenvironment (TME) to promote tumorigenesis was poorly explored. We utilized a computational approach proposed by our previous work, MMP3C (Modeling Metabolic Plasticity by Pathway Pairwise Comparison), to characterize aging-related metabolic plasticity events using pan-cancer bulk RNA-seq data. Our analysis revealed a high degree of metabolically organized heterogeneity across 17 aging-related cancer types. In particular, a higher degree of several energy generation pathways, i.e., glycolysis and impaired oxidative phosphorylation, was observed in older patients. Similar phenomena were also found via single-cell RNA-seq analysis. Furthermore, those energy generation pathways were found to be weakened in activated T cells and macrophages, whereas they increased in exhausted T cells, immunosuppressive macrophages, and Tregs in older patients. It was suggested that aging-induced metabolic switches alter glucose utilization, thereby influencing immune function and resulting in the remodeling of the TME. This work offers new insights into the associations between tumor metabolism and the TME mediated by aging, linking with novel strategies for cancer therapy.


Assuntos
Envelhecimento , Neoplasias , Microambiente Tumoral , Humanos , Envelhecimento/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/genética , Reprogramação Celular , Metabolismo Energético , Glicólise , Reprogramação Metabólica
17.
Crit Rev Oncol Hematol ; : 104541, 2024 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-39461607

RESUMO

Despite recent advancements in the diagnosis and treatment options for cancer, it remains one of the most serious threats to health. Hyperthermia (HT) has emerged as a highly promising area of research due to its safety and cost-effectiveness. Currently, based on temperature, HT can be categorized into thermal ablation and mild hyperthermia. Thermal ablation involves raising the temperature within the tumor to over 60°C, resulting in direct necrosis in the central region of the tumor. In contrast, mild hyperthermia operates at relatively lower temperatures, typically in the range of 41-45°C, to induce damage to tumor cells. Furthermore, HT also serves as an immune adjuvant strategy in radiotherapy, chemotherapy, and immunotherapy, enhancing the effectiveness of radiotherapy, increasing the uptake of chemotherapy drugs, and reprogramming the tumor microenvironment through the induction of immunogenic cell death, thereby promoting the recruitment of endogenous immune cells. This article reviews the current status and development of hyperthermia, outlines potential mechanisms by which hyperthermia inhibits tumors, describes clinical trial attempts combining hyperthermia with radiotherapy, chemotherapy, and immunotherapy, and discusses the relationship between nanoparticles and hyperthermia.

18.
Int Immunopharmacol ; 143(Pt 1): 113282, 2024 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-39383787

RESUMO

Anoikis, a form of programmed cell death induced by loss of cell contact, is closely associated with tumor invasion and metastasis, making it highly significant in lung cancer research. We examined the expression patterns and prognostic relevance of Anoikis-related genes (ARGs) in lung adenocarcinoma (LUAD) using the TCGA-LUAD database. This study identified molecular subtypes associated with Anoikis in LUAD and conducted functional enrichment analyses. We constructed an ARG risk score using univariate least absolute shrinkage and selection operator (LASSO) Cox regression, validated externally with GEO datasets and clinical samples. The clinical applicability of the prognostic model was evaluated using nomograms, calibration curves, decision curve analysis (DCA), and time-dependent AUC assessments. We identified four prognostically significant genes (PLK1, SLC2A1, CDKN3, PHLDA2) and two ARG-related molecular subtypes. ARGs were generally upregulated in LUAD and correlated with multiple pathways including the cell cycle and DNA replication. The prognostic model indicated that the low-risk group had better outcomes and significant correlations with clinicopathological features, tumor microenvironment, immune therapy responses, drug sensitivity, and pan-RNA epigenetic modification-related genes. Patients with low-risk LUAD were potential beneficiaries of immune checkpoint inhibitor (ICI) therapy. Prognostic ARGs' distribution and expression across various immune cell types were further analyzed using single-cell RNA sequencing. The pivotal role of CDKN3 in LUAD was confirmed through qRT-PCR and gene knockout experiments, demonstrating that CDKN3 knockdown inhibits tumor cell proliferation, migration, and invasion. Additionally, we constructed a ceRNA network involving CDKN3/hsa-miR-26a-5p/SNHG6, LINC00665, DUXAP8, and SLC2A1/hsa-miR-218-5p/RNASEH1-AS1, providing new insights for personalized and immune therapy decisions in LUAD patients.

19.
Cancer Cell Int ; 24(1): 331, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39354483

RESUMO

BACKGROUND: Gliomas are aggressive brain tumors with poor prognosis. Understanding the tumor immune microenvironment (TIME) in gliomas is essential for developing effective immunotherapies. This study aimed to identify TIME-related biomarkers in glioma using bioinformatic analysis of RNA-seq data. METHODS: In this study, we employed weighted gene co-expression network analysis (WGCNA) on bulk RNA-seq data to identify TIME-related genes. To identify prognostic genes, we performed univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. Based on these genes, we constructed a prognostic signature and delineated risk groups. To validate the prognostic signature, external validation was conducted. RESULTS: CD8 + T cell infiltration was strongly correlated with glioma patient prognosis. We identified 115 CD8 + T cell-related genes through integrative analysis of bulk-seq data. CDCA5, KIF11, and KIF4A were found to be significant immune-related genes (IRGs) associated with overall survival in glioma patients and served as independent prognostic factors. We developed a prognostic nomogram that incorporated these genes, age, gender, and grade, providing a reliable tool for clinicians to predict patient survival probabilities. The nomogram's predictions were supported by calibration plots, further validating its accuracy. CONCLUSION: In conclusion, our study identifies CD8 + T cell infiltration as a strong predictor of glioma patient outcomes and highlights the prognostic value of genes. The developed prognostic nomogram, incorporating these genes along with clinical factors, provides a reliable tool for predicting patient survival probabilities and has important implications for personalized treatment decisions in glioma.

20.
Apoptosis ; 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39404933

RESUMO

Pulsed electromagnetic field (PEMF) therapy is a potential non-invasive treatment to modulate immune responses and inhibit tumor growth. Cervical cancer (CC) is influenced by IL-37-mediated immune regulation, making PEMF therapy a potential strategy to impede CC progression. This study aimed to elucidate the effects of PEMF on IL-37 regulation and its molecular mechanisms in CC. CC cell-xenografted mouse models, including IL-37 transgenic (IL-37tg) mice, were used to assess tumor growth through in vivo fluorescence imaging and analyze CC cell apoptosis via flow cytometry. TCGA-CESC transcriptome and clinical data were analyzed to identify key inflammation and immune-related genes. CD8+ T cell models were stimulated with PEMF, and apoptosis, oxidative stress, and inflammatory factor expression were analyzed through RT-qPCR, Western blot, and flow cytometry. PEMF treatment significantly inhibited IL-37 expression (p < 0.05), promoted inflammatory factor release (TNF-α and IL-6), and activated oxidative stress, leading to increased CC cell apoptosis (p < 0.05). IL-37 interaction with SMAD3 impacted the p38/NF-κB signaling pathway, modulating CD8+ T cell activity and cytotoxicity. Co-culture of Hela cells with CD8+ T cells under PEMF treatment showed reduced proliferation (by 40%), migration, and invasion (p < 0.05). In vivo experiments with CC-bearing mice demonstrated that PEMF treatment downregulated IL-37 expression (p < 0.05), enhanced CD8+ T cell function, and inhibited tumor growth (p < 0.05). These molecular mechanisms were validated through RT-qPCR, Western blot, and immunohistochemistry. Thus, PEMF therapy inhibits CC progression by downregulating IL-37 and improving CD8+ T cell function via the SMAD3/p38/NF-κB signaling pathway.

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