RESUMO
Tumor-associated inflammation drives cancer progression and therapy resistance, often linked to the infiltration of monocyte-derived tumor-associated macrophages (TAMs), which are associated with poor prognosis in various cancers. To advance immunotherapies, testing on immunocompetent pre-clinical models of human tissue is crucial. We have developed an in vitro model of microvascular networks with tumor spheroids or patient tissues to assess monocyte trafficking into tumors and evaluate immunotherapies targeting the human tumor microenvironment. Our findings demonstrate that macrophages in vascularized breast and lung tumor models can enhance monocyte recruitment via CCL7 and CCL2, mediated by CSF-1R. Additionally, a multispecific antibody targeting CSF-1R, CCR2, and neutralizing TGF-ß (CSF1R/CCR2/TGF-ß Ab) repolarizes TAMs towards an anti-tumoral M1-like phenotype, reduces monocyte chemoattractant protein secretion, and blocks monocyte migration. This antibody also inhibits monocyte recruitment in patient-specific vascularized tumor models. In summary, this vascularized tumor model recapitulates the monocyte recruitment cascade, enabling functional testing of innovative therapeutic antibodies targeting TAMs in the tumor microenvironment.
Assuntos
Monócitos , Receptor de Fator Estimulador de Colônias de Macrófagos , Receptores CCR2 , Microambiente Tumoral , Humanos , Receptores CCR2/metabolismo , Receptores CCR2/antagonistas & inibidores , Monócitos/metabolismo , Monócitos/imunologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral , Feminino , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Camundongos , Movimento Celular/efeitos dos fármacos , Neoplasias/imunologia , Neoplasias/patologiaRESUMO
Background: Cellular senescence (CS) is believed to be a major factor in the evolution of cancer. However, CS-related lncRNAs (CSRLs) involved in colon cancer regulation are not fully understood. Our goal was to create a novel CSRLs prognostic model for predicting prognosis and immunotherapy and exploring its potential molecular function in colon cancer. Methods: The mRNA sequencing data and relevant clinical information of GDC TCGA Colon Cancer (TCGA-COAD) were obtained from UCSC Xena platform, and CS-associated genes was acquired from the CellAge website. Pearson correlation analysis was used to identify CSRLs. Then we used Kaplan-Meier survival curve analysis and univariate Cox analysis to acquire prognostic CSRL. Next, we created a CSRLs prognostic model using LASSO and multivariate Cox analysis, and evaluated its prognostic power by Kaplan-Meier and ROC curve analysis. Besides, we explored the difference in tumor microenvironment, somatic mutation, immunotherapy, and drug sensitivity between high-risk and low-risk groups. Finally, we verified the functions of MYOSLID in cell experiments. Results: Three CSRLs (AC025165.1, LINC02257 and MYOSLID) were identified as prognostic CSRLs. The prognostic model exhibited a powerful predictive ability for overall survival and clinicopathological features in colon cancer. Moreover, there was a significant difference in the proportion of immune cells and the expression of immunosuppressive point biomarkers between the different groups. The high-risk group benefited from the chemotherapy drugs, such as Teniposide and Mitoxantrone. Finally, cell proliferation and CS were suppressed after MYOSLID knockdown. Conclusion: CSRLs are promising biomarkers to forecast survival and therapeutic responses in colon cancer patients. Furthermore, MYOSLID, one of 3-CSRLs in the prognostic model, could dramatically regulate the proliferation and CS of colon cancer.
Assuntos
Biomarcadores Tumorais , Senescência Celular , Neoplasias do Colo , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante , Microambiente Tumoral , RNA Longo não Codificante/genética , Neoplasias do Colo/genética , Neoplasias do Colo/imunologia , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Humanos , Prognóstico , Senescência Celular/genética , Senescência Celular/imunologia , Biomarcadores Tumorais/genética , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Feminino , Masculino , Pessoa de Meia-Idade , Linhagem Celular TumoralRESUMO
Purines and pyrimidines are signaling molecules in the tumor microenvironment that affect cancer immunity. The purinergic signaling pathways have been shown to play an important role in the development and progression of cancer. CD39 and CD73 are ectonucleotidases responsible for breaking down ATP or ADP into adenosine, which regulates immunosuppression in various types of cancer. These enzymes have been studied as a potential therapeutic target in immunotherapy, and recent research suggests a correlation between ectonucleotidases and clinical outcomes in cancer.Prostate cancer is the most diagnosed cancer in men, after non-melanoma skin tumors, and is the second leading cause of death in men in the world. Despite having long survival periods, patients often receive excessive or insufficient treatment. Within this complex landscape, the adenosine/CD73 pathway plays a crucial role. Therefore, this review aims to highlight new findings on the potential role of purinergic signaling in cancer treatment and emphasizes the importance of anti-CD73 as a pharmacological strategy for prostate cancer therapy.
Assuntos
5'-Nucleotidase , Neoplasias da Próstata , Transdução de Sinais , Humanos , 5'-Nucleotidase/metabolismo , 5'-Nucleotidase/imunologia , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Proteínas Ligadas por GPI/metabolismo , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/imunologia , Microambiente Tumoral/imunologia , Adenosina/metabolismo , Imunoterapia/métodos , Terapia de Alvo MolecularRESUMO
Background: Immunotherapy has revolutionized skin cutaneous melanoma treatment, but response variability due to tumor heterogeneity necessitates robust biomarkers for predicting immunotherapy response. Methods: We used weighted gene co-expression network analysis (WGCNA), consensus clustering, and 10 machine learning algorithms to develop the immunotherapy-related gene model (ITRGM) signature. Multi-omics analyses included bulk and single-cell RNA sequencing of melanoma patients, mouse bulk RNA sequencing, and pathology sections of melanoma patients. Results: We identified 66 consensus immunotherapy prognostic genes (CITPGs) using WGCNA and differentially expressed genes (DEGs) from two melanoma cohorts. The CITPG-high group showed better prognosis and enriched immune activities. DEGs between CITPG-high and CITPG-low groups in the TCGA-SKCM cohort were analyzed in three additional melanoma cohorts using univariate Cox regression, resulting in 44 consensus genes. Using 101 machine learning algorithm combinations, we constructed the ITRGM signature based on seven model genes. The ITRGM outperformed 37 published signatures in predicting immunotherapy prognosis across the training cohort, three testing cohorts, and a meta-cohort. It effectively stratified patients into high-risk or low-risk groups for immunotherapy response. The low-risk group, with high levels of model genes, correlated with increased immune characteristics such as tumor mutation burden and immune cell infiltration, indicating immune-hot tumors with a better prognosis. The ITRGM's relationship with the tumor immune microenvironment was further validated in our experiments using pathology sections with GBP5, an important model gene, and CD8 IHC analysis. The ITRGM also predicted better immunotherapy response in eight cohorts, including urothelial carcinoma and stomach adenocarcinoma, indicating broad applicability. Conclusions: The ITRGM signature is a stable and robust predictor for stratifying melanoma patients into 'immune-hot' and 'immune-cold' tumors, enhancing prognosis and response to immunotherapy.
Assuntos
Biomarcadores Tumorais , Imunoterapia , Aprendizado de Máquina , Melanoma , Humanos , Melanoma/terapia , Melanoma/imunologia , Melanoma/genética , Imunoterapia/métodos , Biomarcadores Tumorais/genética , Prognóstico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/genética , Animais , Perfilação da Expressão Gênica , Transcriptoma , Regulação Neoplásica da Expressão Gênica , Camundongos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Resultado do Tratamento , Redes Reguladoras de GenesRESUMO
This mini review summarizes the immunobiology of myelodysplastic syndromes, specifically focusing on the interactions between immune cells, cytokines, and dysplastic cells within the tumor microenvironment in the bone marrow. We elucidate in detail how immune dysregulation and evasion influence the initiation and progression of myelodysplastic syndromes, as well as resistance to therapy and progression to AML. In addition, we highlight a range of therapeutic strategies, including the most recent breakthroughs and experimental therapies for treating MDS. Finally, we address the existing knowledge gaps in the understanding of the immunobiology of MDS and propose future research directions, promising advancements toward enhancing clinical outcomes and survival for patients with MDS.
Assuntos
Síndromes Mielodisplásicas , Microambiente Tumoral , Humanos , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/terapia , Microambiente Tumoral/imunologia , Citocinas/metabolismo , Citocinas/imunologia , Animais , Medula Óssea/imunologia , Medula Óssea/patologia , Progressão da DoençaRESUMO
The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway in hepatocellular carcinoma (HCC) is limited. NOD-like receptors (NLRs) comprise a highly evolutionarily conserved family of cytosolic bacterial sensors, yet their impact on antitumor immunity against HCC remains unclear. In this study, we uncovered that NOD1, a well-studied member of NLR family, exhibits predominant expression in tumor-associated macrophages (TAMs) and correlates positively with improved prognosis and responses to anti-PD-1 treatments in patients with HCC. Activation of NOD1 in vivo augments antitumor immunity and enhances the effectiveness of anti-PD-1 therapy. Mechanistically, NOD1 activation resulted in diminished expression of perilipin 5, thereby hindering fatty acid oxidation and inducing free fatty acid accumulation in TAMs. This metabolic alteration promoted membrane localization of the costimulatory molecule OX40L in a lipid modification-dependent manner, thereby activating CD8+ T cells. These findings unveil a previously unrecognized role for NOD1 in fortifying antitumor T cell immunity in HCC, potentially advancing cancer immunotherapy.
Assuntos
Linfócitos T CD8-Positivos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteína Adaptadora de Sinalização NOD1 , Macrófagos Associados a Tumor , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , Animais , Humanos , Camundongos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Linhagem Celular Tumoral , Imunoterapia/métodos , Masculino , Microambiente Tumoral/imunologiaRESUMO
Multiple myeloma (MM) is currently treated with combined immunotherapies targeting the immune microenvironment surrounding MM cells. Although novel immunotherapeutic agents for MM have improved complete response rates and survival time, some patients experience repeated relapses and die of MM because its progression is strongly influenced by the immune microenvironment as well as cytogenetic abnormalities of MM cells. Various studies have elucidated the mechanisms underlying the immunosuppressive immune microenvironment of MM. Recently, single-cell RNA sequencing and cytometry by time-of-flight analysis have revealed spatiotemporal crosstalk between MM and immune cells in the bone marrow of patients with MM. These studies showed that immunosuppression appears in the early stages of MM and becomes stronger as the disease progresses, leading to immunotherapy resistance. Understanding the state of the immune microenvironment in patients with MM is important for developing immunotherapeutic strategies for long-term complete response and cure.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Imunoterapia , Mieloma Múltiplo , Microambiente Tumoral , Mieloma Múltiplo/terapia , Mieloma Múltiplo/imunologia , Humanos , Microambiente Tumoral/imunologiaRESUMO
Background: Intrahepatic cholangiocarcinoma (ICC) is a disease with poor prognosis and limited therapeutic options. We investigated the tumor immune microenvironment (TIME) to identify predictors of disease outcome and to explore targets for therapeutic modulation. Methods: Liver tissue samples were collected during 2008-2019 from patients (n = 139) diagnosed with ICC who underwent curative intent surgery without neoadjuvant chemotherapy. Samples from the discovery cohort (n = 86) were immunohistochemically analyzed on tissue microarrays (TMAs) for the expression of CD68, CD3, CD4, CD8, Foxp3, PD-L1, STAT1, and p-STAT1 in tumor core and stroma areas. Results were digitally analyzed using QuPath software and correlated with clinicopathological characteristics. For validation of TIME-related biomarkers, we performed multiplex imaging mass cytometry (IMC) in a validation cohort (n = 53). Results: CD68+ cells were the predominant immune cell type in the TIME of ICC. CD4+high T cell density correlated with better overall survival (OS). Prediction modeling together with validation cohort confirmed relevance of CD4+ cells, PD-L1 expression by immune cells in the stroma and N-stage on overall disease outcome. In turn, IMC analyses revealed that silent CD3+CD4+ clusters inversely impacted survival. Among annotated immune cell clusters, PD-L1 was most relevantly expressed by CD4+FoxP3+ cells. A subset of tumors with high density of immune cells ("hot" cluster) correlated with PD-L1 expression and could identify a group of candidates for immune checkpoint inhibition (ICI). Ultimately, higher levels of STAT1 expression were associated with higher lymphocyte infiltration and PD-L1 expression. Conclusions: These results highlight the importance of CD4+ T cells in immune response against ICC. Secondly, a subset of tumors with "hot" TIME represents potential candidates for ICI, while stimulation of STAT1 pathway could be a potential target to turn "cold" into "hot" TIME in ICC.
The tumor immune microenvironment (TIME) plays a critical role in the immune response In many cancers, including intrahepatic cholangiocarcinoma (ICC). Molecular subtyping of the ICC microenvironment already revealed inter-tumoral heterogeneity with variant profiles of immune cell infiltrates. A recent study created an in-depth immune cell atlas of the TIME in biliary tract cancers and could demonstrate the relevance of specific immune cell subpopulations on patient outcome. We are able to provide a distinctive characterization of TIME, separating tumor epithelial- and stroma areas, in a large and representative ICC cohort using digitalized image analysis on tissue microarrays (TMA) as well as multiplex imaging mass cytometry (IMC). The study was designed for identification of immune cell prognosticators allocating institutional ICC patients into a discovery (200815) and a validation (201019) cohort. Immune cell subpopulations were correlated with clinicopathological characteristics and patient outcome. Our results highlight: i. The important role of CD4+ T cell infiltration in ICC patients; ii. ICC tumors with high density of immune cells associated with PD-L1 expression identifies a subset of patients with variant tumor biology; iii. Stimulation of STAT1 pathway may be a relevant target to turn "cold" into "hot" tumors.
Assuntos
Antígeno B7-H1 , Neoplasias dos Ductos Biliares , Biomarcadores Tumorais , Colangiocarcinoma , Microambiente Tumoral , Humanos , Colangiocarcinoma/imunologia , Colangiocarcinoma/patologia , Microambiente Tumoral/imunologia , Masculino , Feminino , Neoplasias dos Ductos Biliares/imunologia , Neoplasias dos Ductos Biliares/patologia , Pessoa de Meia-Idade , Prognóstico , Idoso , Biomarcadores Tumorais/metabolismo , Antígeno B7-H1/metabolismo , Fator de Transcrição STAT1/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Antígenos CD/metabolismo , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Molécula CD68RESUMO
Ferroptosis is a new form of cell death that differs from traditional forms of death. It is ferroptosis-dependent lipid peroxidation death. Colorectal cancer(CRC) is the most common tumor in the gastrointestinal tract with a long occultation period and a poor five-year prognosis. Exploring effective systemic treatments for CRC remains a great challenge worldwide. Numerous studies have demonstrated that ferroptosis can participate in the biological malignant process of various tumor, including CRC, so understanding the role and regulatory mechanisms of ferroptosis in CRC plays a crucial role in the treatment of CRC. In this paper, we reviews the mechanisms of ferroptosis in CRC, the associated regulatory factors and their interactions with various immune cells in the immune microenvironment. In addition, targeting ferroptosis has emerged as an encouraging strategy for CRC treatment. Finally, to inform subsequent research and clinical diagnosis and treatment, we review therapeutic approaches to CRC radiotherapy, immunotherapy, and herbal therapy targeting ferroptosis.
Assuntos
Neoplasias Colorretais , Ferroptose , Microambiente Tumoral , Humanos , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Microambiente Tumoral/imunologia , Animais , Imunoterapia/métodosRESUMO
Patients with Immune-Mediated Inflammatory Diseases (IMIDs) are known to have an elevated risk of developing cancer, but the exact causative factors remain subject to ongoing debate. This narrative review aims to present the available evidence concerning the intricate relationship between these two conditions. Environmental influences and genetic predisposition lead to a dysregulated immune response resulting in chronic inflammation, which is crucial in the pathogenesis of IMIDs and oncogenic processes. Mechanisms such as the inflammatory microenvironment, aberrant intercellular communication due to abnormal cytokine levels, excessive reparative responses, and pathological angiogenesis are involved. The chronic immunosuppression resulting from IMIDs treatments further adds to the complexity of the pathogenic scenario. In conclusion, this review highlights critical gaps in the current literature, suggesting potential avenues for future research. The intricate interplay between IMIDs and cancer necessitates more investigation to deepen our understanding and improve patient management.
Assuntos
Inflamação , Neoplasias , Humanos , Neoplasias/imunologia , Neoplasias/etiologia , Inflamação/imunologia , Animais , Citocinas/metabolismo , Citocinas/imunologia , Predisposição Genética para Doença , Microambiente Tumoral/imunologiaRESUMO
Osteosarcoma has a unique tumor microenvironment (TME), which is characterized as a complex microenvironment comprising of bone cells, immune cells, stromal cells, and heterogeneous vascular structures. These elements are intricately embedded in a mineralized extracellular matrix, setting it apart from other primary TMEs. In a state of normal physiological function, these cell types collaborate in a coordinated manner to maintain the homeostasis of the bone and hematopoietic systems. However, in the pathological condition, i.e., neoplastic malignancies, the tumor-immune microenvironment (TIME) has been shown to promote cancer cells proliferation, migration, apoptosis and drug resistance, as well as immune escape. The intricate and dynamic system of the TIME in osteosarcoma involves crucial roles played by various infiltrating cells, the complement system, and exosomes. This complexity is closely associated with tumor cells evading immune surveillance, experiencing uncontrolled proliferation, and facilitating metastasis. In this review, we elucidate the intricate interplay between diverse cell populations in the osteosarcoma TIME, each contributing uniquely to tumor progression. From chondroblastic and osteoblastic osteosarcoma cells to osteoclasts, stromal cells, and various myeloid and lymphoid cell subsets, the comprehensive single-cell analysis provides a detailed roadmap of the complex osteosarcoma ecosystem. Furthermore, we summarize the mutations, epigenetic mechanisms, and extracellular vesicles that dictate the immunologic landscape and modulate the TIME of osteosarcoma. The perspectives of the clinical implementation of immunotherapy and therapeutic approaches for targeting immune cells are also intensively discussed.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Microambiente Tumoral , Osteossarcoma/imunologia , Osteossarcoma/patologia , Humanos , Microambiente Tumoral/imunologia , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/patologia , Animais , Evasão TumoralRESUMO
Recent advances in cancer research have highlighted the pivotal role of tertiary lymphoid structures (TLSs) in modulating immune responses, particularly in breast cancer (BRCA). Here, we performed an integrated analysis of bulk transcriptome data from over 6000 BRCA samples using biological network-based computational strategies and machine learning (ML) methods, and identified LGALS2 as a key marker within TLSs. Single-cell sequencing and spatial transcriptomics uncover the role of LGALS2 in TLS-associated dendritic cells (DCs) stimulation and reveal the complexity of the tumor microenvironment (TME) at both the macro and micro levels. Elevated LGALS2 expression correlates with prolonged survival, which is associated with a robust immune response marked by diverse immune cell infiltration and active anti-tumor pathways leading to a 'hot' tumor microenvironment. The colocalization of LGALS2 with TLS-associated DCs and its role in immune activation in BRCA were confirmed by hematoxylin-eosin (HE), immunohistochemistry (IHC), and in vivo validation analyses. The identification of LGALS2 as a key factor in BRCA not only highlights its therapeutic potential in novel TLS-directed immunotherapy but also opens new avenues in patient stratification and treatment selection, ultimately improving clinical management.
Assuntos
Neoplasias da Mama , Células Dendríticas , Galectina 2 , Imunoterapia , Estruturas Linfoides Terciárias , Microambiente Tumoral , Humanos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Feminino , Microambiente Tumoral/imunologia , Imunoterapia/métodos , Estruturas Linfoides Terciárias/imunologia , Estruturas Linfoides Terciárias/patologia , Galectina 2/genética , Galectina 2/metabolismo , Animais , Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Camundongos , Análise de Célula Única , PrognósticoRESUMO
BACKGROUND: Immunotherapy presents both promises and challenges in treating hepatocellular carcinoma (HCC) due to its complex immunological microenvironment. The role of B cells, a key part of the immune system, remains uncertain in HCC. AIM: To identify B-cell-specific signatures and reveal novel immunophenotyping and therapeutic targets for HCC. METHODS: Using the Tumor Immune Single-cell Hub 2 database, we identified B-cell-related genes (BRGs) in HCC. Gene enrichment analysis was performed to explore the possible collaboration between B cells and T cells in HCC. We conducted univariate Cox regression analysis using The Cancer Genome Atlas liver HCC collection dataset to find BRGs linked to HCC prognosis. Subsequently, least absolute shrinkage and selection operator regression was utilized to develop a prognostic model with 11 BRGs. The model was validated using the International Cancer Genome Consortium dataset and GSE76427. RESULTS: The risk score derived from the prognostic model emerged as an independent prognostic factor for HCC. Analysis of the immune microenvironment and cell infiltration revealed the immune status of various risk groups, supporting the cooperation of B and T cells in suppressing HCC. The BRGs model identified new molecular subtypes of HCC, each with distinct immune characteristics. Drug sensitivity analysis identified targeted drugs effective for each HCC subtype, enabling precision therapy and guiding clinical decisions. CONCLUSION: We clarified the role of B cells in HCC and propose that the BRGs model offers promising targets for personalized immunotherapy.
Assuntos
Linfócitos B , Carcinoma Hepatocelular , Imunofenotipagem , Neoplasias Hepáticas , Microambiente Tumoral , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/tratamento farmacológico , Microambiente Tumoral/imunologia , Imunofenotipagem/métodos , Prognóstico , Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacos , Imunoterapia/métodos , Biomarcadores Tumorais/genética , Masculino , Regulação Neoplásica da Expressão Gênica , Terapia de Alvo Molecular/métodos , Feminino , Linfócitos T/imunologia , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodosRESUMO
Tumor associated macrophages (TAMs) are the predominant innate immune cells in the tumor microenvironment (TME). Cytokines induce the differentiation of macrophages into distinct types of TAMs, primarily characterized by two phenotypes: M1-polarized and M2-polarized. Cancer growth is suppressed by M1-polarized macrophages and promoted by M2-polarized macrophages. The regulation of macrophage M1 polarization has emerged as a promising strategy for cancer immunotherapy. Polysaccharides are important bioactive substances found in numerous plants, manifesting a wide range of noteworthy biological actions, such as immunomodulation, anti-tumor effects, antioxidant capabilities, and antiviral functions. In recent years, there has been a significant increase in interest regarding the immunomodulatory and anti-tumor properties of polysaccharides derived from plants. The regulatory impact of polysaccharides on the immune system is mainly associated with the natural immune response, especially with the regulation of macrophages. This review provides a thorough analysis of the regulatory effects and mechanisms of plant polysaccharides on TAMs. Additionally, an analysis of potential opportunities for clinical translation of plant polysaccharides as immune adjuvants is presented. These insights have greatly advanced the research of plant polysaccharides for immunotherapy in tumor-related applications.
Assuntos
Imunoterapia , Neoplasias , Polissacarídeos , Microambiente Tumoral , Macrófagos Associados a Tumor , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Polissacarídeos/farmacologia , Imunoterapia/métodos , Animais , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismoRESUMO
Prostate adenocarcinoma (PRAD) is a prevalent global malignancy which depends more on lipid metabolism for tumor progression compared to other cancer types. Although Stearoyl-coenzyme A desaturase (SCD) is documented to regulate lipid metabolism in multiple cancers, landscape analysis of its implications in PRAD are still missing at present. Here, we conducted an analysis of diverse cancer datasets revealing elevated SCD expression in the PRAD cohort at both mRNA and protein levels. Interestingly, the elevated expression was associated with SCD promoter hypermethylation and genetic alterations, notably the L134V mutation. Integration of comprehensive tumor immunological and genomic data revealed a robust positive correlation between SCD expression levels and the abundance of CD8+ T cells and macrophages. Further analyses identified significant associations between SCD expression and various immune markers in tumor microenvironment. Single-cell transcriptomic profiling unveiled differential SCD expression patterns across distinct cell types within the prostate tumor microenvironment. The Gene Ontology and Kyoto Encyclopedia of Genes and Genome analyses showed that SCD enriched pathways were primarily related to lipid biosynthesis, cholesterol biosynthesis, endoplasmic reticulum membrane functions, and various metabolic pathways. Gene Set Enrichment Analysis highlighted the involvement of elevated SCD expression in crucial cellular processes, including the cell cycle and biosynthesis of cofactors pathways. In functional studies, SCD overexpression promoted the proliferation, metastasis and invasion of prostate cancer cells, whereas downregulation inhibits these processes. This study provides comprehensive insights into the multifaceted roles of SCD in PRAD pathogenesis, underscoring its potential as both a therapeutic target and prognostic biomarker.
Assuntos
Adenocarcinoma , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata , Estearoil-CoA Dessaturase , Microambiente Tumoral , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Humanos , Masculino , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Metilação de DNARESUMO
The human microbiome has recently emerged as a focal point in cancer research, specifically in anti-tumor immunity, immunotherapy, and chemotherapy. This review explores microbial-derived metabolites, emphasizing their crucial roles in shaping fundamental aspects of cancer treatment. Metabolites such as short-chain fatty acids (SCFAs), Trimethylamine N-Oxide (TMAO), and Tryptophan Metabolites take the spotlight, underscoring their diverse origins and functions and their profound impact on the host immune system. The focus is on SCFAs' remarkable ability to modulate immune responses, reduce inflammation, and enhance anti-tumor immunity within the intricate tumor microenvironment (TME). The review critically evaluates TMAO, intricately tied to dietary choices and gut microbiota composition, assessing its implications for cancer susceptibility, progression, and immunosuppression. Additionally, the involvement of tryptophan and other amino acid metabolites in shaping immune responses is discussed, highlighting their influence on immune checkpoints, immunosuppression, and immunotherapy effectiveness. The examination extends to their dynamic interaction with chemotherapy, emphasizing the potential of microbial-derived metabolites to alter treatment protocols and optimize outcomes for cancer patients. A comprehensive understanding of their role in cancer therapy is attained by exploring their impacts on drug metabolism, therapeutic responses, and resistance development. In conclusion, this review underscores the pivotal contributions of microbial-derived metabolites in regulating anti-tumor immunity, immunotherapy responses, and chemotherapy outcomes. By illuminating the intricate interactions between these metabolites and cancer therapy, the article enhances our understanding of cancer biology, paving the way for the development of more effective treatment options in the ongoing battle against cancer.
Assuntos
Ácidos Graxos Voláteis , Microbioma Gastrointestinal , Imunoterapia , Neoplasias , Triptofano , Microambiente Tumoral , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Imunoterapia/métodos , Microbioma Gastrointestinal/imunologia , Microambiente Tumoral/imunologia , Animais , Ácidos Graxos Voláteis/metabolismo , Triptofano/metabolismo , Metilaminas/metabolismo , Metilaminas/imunologia , Antineoplásicos/uso terapêuticoRESUMO
Glioblastoma is an aggressive primary brain tumor that poses many therapeutic difficulties because of the high rate of proliferation, genetic variability, and its immunosuppressive microenvironment. The theory of cancer immunoediting, which includes the phases of elimination, equilibrium, and escape, offers a paradigm for comprehending interactions between the immune system and glioblastoma. Immunoediting indicates the process by which immune cells initially suppress tumor development, but thereafter select for immune-resistant versions leading to tumor escape and progression. The tumor microenvironment (TME) in glioblastoma is particularly immunosuppressive, with regulatory T cells and myeloid-derived suppressor cells being involved in immune escape. To achieve an efficient immunotherapy for glioblastoma, it is crucial to understand these mechanisms within the TME. Existing immunotherapeutic modalities such as chimeric antigen receptor T cells and immune checkpoint inhibitors have been met with some level of resistance because of the heterogeneous nature of the immune response to glioblastoma. Solving these issues is critical to develop novel strategies capable of modulating the TME and re-establishing normal immune monitoring. Further studies should be conducted to identify the molecular and cellular events that underlie the immunosuppressive tumor microenvironment in glioblastoma. Comprehending and modifying the stages of immunoediting in glioblastoma could facilitate the development of more potent and long-lasting therapies.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Imunoterapia , Microambiente Tumoral , Glioblastoma/imunologia , Glioblastoma/terapia , Humanos , Microambiente Tumoral/imunologia , Imunoterapia/métodos , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Evasão Tumoral/imunologiaRESUMO
Tumor immune microenvironment (TIME) spatial organization predicts outcome and therapy response in triple-negative breast cancer (TNBC). An immunosuppressive TIME containing elevated tumor-associated macrophages (TAM) and scarce CD8+ T cells is associated with poor outcome, but the regulatory mechanisms are poorly understood. Here we show that ETS1-driven caspase-1 expression, required for IL1ß processing and TAM recruitment, is negatively regulated by estrogen receptors alpha (ERα) and a defining feature of TNBC. Elevated tumoral caspase-1 is associated with a distinct TIME characterized by increased pro-tumoral TAMs and CD8+ T cell exclusion from tumor nests. Mouse models prove the functional importance of ERα, ETS1, caspase-1 and IL1ß in TIME conformation. Caspase-1 inhibition induces an immunoreactive TIME and reverses resistance to immune checkpoint blockade, identifying a therapeutically targetable mechanism that governs TNBC spatial organization.
Assuntos
Linfócitos T CD8-Positivos , Caspase 1 , Receptor alfa de Estrogênio , Imunoterapia , Interleucina-1beta , Proteína Proto-Oncogênica c-ets-1 , Neoplasias de Mama Triplo Negativas , Microambiente Tumoral , Macrófagos Associados a Tumor , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Animais , Feminino , Humanos , Microambiente Tumoral/imunologia , Camundongos , Imunoterapia/métodos , Caspase 1/metabolismo , Receptor alfa de Estrogênio/metabolismo , Linhagem Celular Tumoral , Proteína Proto-Oncogênica c-ets-1/metabolismo , Proteína Proto-Oncogênica c-ets-1/genética , Interleucina-1beta/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Regulação Neoplásica da Expressão GênicaRESUMO
Glycolytic metabolic reprogramming in cancer is regulated by both cancer intrinsic variations like isocitrate dehydrogenase 1 (IDH1) status and non-cancerous microenvironment components like tumor associated macrophages (TAMs). However, the detailed mechanism remains elusive. Here, we identify hexosaminidase B (HEXB) as a key regulator for glycolysis in glioblastoma (GBM). HEXB intercellularly manipulates TAMs to promote glycolysis in GBM cells, while intrinsically enhancing cancer cell glycolysis. Mechanistically, HEXB elevation augments tumor HIF1α protein stability through activating ITGB1/ILK/YAP1; Subsequently, HIF1α promotes HEXB and multiple glycolytic gene transcription in GBM cells. Genetic ablation and pharmacological inhibition of HEXB elicits substantial therapeutic effects in preclinical GBM models, while targeting HEXB doesn't induce significant reduction in IDH1 mutant glioma and inhibiting IDH1 mutation-derived 2-hydroxyglutaric acid (2-HG) significantly restores HEXB expression in glioma cells. Our work highlights a HEXB driven TAMs-associated glycolysis-promoting network in GBM and provides clues for developing more effective therapies against it.
Assuntos
Neoplasias Encefálicas , Carcinogênese , Glioblastoma , Glicólise , Subunidade alfa do Fator 1 Induzível por Hipóxia , Isocitrato Desidrogenase , beta-N-Acetil-Hexosaminidases , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Linhagem Celular Tumoral , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Carcinogênese/genética , Camundongos , beta-N-Acetil-Hexosaminidases/metabolismo , beta-N-Acetil-Hexosaminidases/genética , Microambiente Tumoral/imunologia , Regulação Neoplásica da Expressão Gênica , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/imunologia , Integrina beta1/metabolismo , Integrina beta1/genética , Glutaratos/metabolismo , Mutação , Proteínas de Sinalização YAP/metabolismoRESUMO
BACKGROUND: Positive regulators of T-cell function (PTFRs), integral to T-cell proliferation and activation, have been identified as potential prognostic markers in colorectal cancer (CRC). Despite this, their role within the tumor microenvironment (TME) and their response to immunotherapy are not yet fully understood. METHODS: This study delved into PTFR-related CRC subtypes by analyzing four independent transcriptome datasets, emphasizing the most significant prognostic PTFRs. We identified differentially expressed genes (DEGs) between two subtypes and developed a PTFR risk model using LASSO and Cox regression methods. The model's associations with survival time, clinical features, TME characteristics, tumor mutation profiles, microsatellite instability (MSI), cancer stem cell (CSC) index, and responses to chemotherapy, targeted therapy, and immunotherapy were subsequently explored. RESULTS: The PTFR risk model demonstrated a strong predictive capacity for CRC. It facilitated the estimation of immune cell composition, HLA expression levels, immune checkpoint expression, mutation burden, CSC index features, and the effectiveness of immunotherapy. CONCLUSIONS: This study enhances our understanding of the role of PTFRs in CRC progression and introduces an innovative assessment framework for CRC immunotherapy. This framework improves the prediction of treatment outcomes and aids in the customization of therapeutic strategies.