RESUMO
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
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
The gut microbiota plays an important role in the development and treatment of hepatocellular carcinoma (HCC). However, the implication of specific gut microbiota in targeted sorafenib therapy for advanced HCC and the microbiota mode of action, remain to be elucidated. Here, we confirmed that four bacterial genera, Lachnoclostridium, Lachnospira, Enterobacter and Enterococcus, are associated with the therapeutic efficacy of Sorafenib, and that Enterobacter faecium (Efm) plays a crucial role in modulating the sorafenib activity. The effective colonization by Emf induced the IL-12 and IFN-γ production and an increased proportion of IFN-γ+CD8+ T cells in the tumor microenvironment. Finally, exopolysaccharides (EPS) from Efm were the primary inducer to prompt IFN-γ+CD8+ T cells to secrete IFN-γ, which together with sorafenib instigated ferroptosis in HCC cells. Collectively, these results indicate that Efm is a promising probiotics that enhances the efficacy of sorafenib treatment in advanced HCC.
Assuntos
Linfócitos T CD8-Positivos , Carcinoma Hepatocelular , Enterococcus faecium , Ferroptose , Interferon gama , Neoplasias Hepáticas , Sorafenibe , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/microbiologia , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/microbiologia , Interferon gama/metabolismo , Interferon gama/imunologia , Humanos , Enterococcus faecium/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Animais , Ferroptose/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Probióticos/farmacologia , Masculino , Microambiente Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral , Antineoplásicos/farmacologiaRESUMO
Neoantigen vaccines represent an emerging and promising strategy in the field of tumor immunotherapy. Despite their potential, designing an effective neoantigen vaccine remains a challenge due to the current limitations in predicting CD4+ T cell epitopes with high accuracy. Here, we introduce a novel approach to neoantigen vaccine design that does not rely on computational prediction of CD4+ T cell epitopes. Utilizing nitrated helper T cell epitope containing p-nitrophenylalanine, termed "NitraTh epitope," we have successfully engineered a series of tumor neoantigen vaccines capable of eliciting robust neoantigen-specific immune responses. With the help of NitraTh epitope, even mutations with low predicted affinity for MHC class I molecules were successfully induced to elicit neoantigen-specific responses. In H22 cell allograft and patient-derived xenograft (PDX) liver cancer mouse models, the NitraTh epitope-based neoantigen vaccines significantly suppressed tumor progression. More strikingly, through single-cell sequencing we found that the NitraTh epitope-based neoantigen vaccines regulate macrophage reprogramming and modulate macrophages to decrease the levels of the immunosuppressive molecule prostaglandin E2 (PGE2), which in turn reshapes the tumor immunosuppressive microenvironment. In summary, NitraTh epitope-based neoantigen vaccines possess the dual effects of potently activating neoantigen-specific immunity and alleviating immunosuppression, potentially providing a new paradigm for the design of tumor neoantigen vaccines.
Assuntos
Antígenos de Neoplasias , Vacinas Anticâncer , Imunoterapia , Vacinas Anticâncer/imunologia , Animais , Camundongos , Humanos , Imunoterapia/métodos , Antígenos de Neoplasias/imunologia , Epitopos de Linfócito T/imunologia , Microambiente Tumoral/imunologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Neoplasias/imunologia , Neoplasias/terapia , Ensaios Antitumorais Modelo de Xenoenxerto , FemininoRESUMO
BACKGROUND: Myeloid-derived suppressor cells (MDSCs) play a pivotal role in immunosuppression and tumor progression in hepatocellular carcinoma (HCC). While various treatments like surgical resection, ablation, and radiotherapy have been studied for their effects on circulating MDSC frequencies in HCC patients, the findings remain inconclusive. Transarterial Chemoembolization (TACE) stands as the standard care for unresectable HCC, with Microparticle TACE (mTACE) gaining prominence for its capacity to induce significant tumor necrosis. However, the immunological ramifications of such pathological outcomes are scarcely reported. METHODS AND RESULTS: This study aims to elucidate the alterations in MDSC subtypes, specifically monocytic MDSCs (mMDSCs) and early-stage MDSCs (eMDSCs), post-mTACE and to investigate their clinical correlations in HCC patients. A cohort comprising 75 HCC patients, 16 liver cirrhosis patients, and 20 healthy controls (HC) was studied. Peripheral blood samples were collected and analyzed for MDSC subtypes. The study also explored the associations between MDSC frequencies and various clinical parameters in HCC patients. The frequency of mMDSCs was significantly elevated in the HCC group compared to liver cirrhosis and HC. Importantly, mMDSC levels were strongly correlated with aggressive clinical features of HCC, including tumor size, vascular invasion, and distant metastasis. Post-mTACE, a marked reduction in mMDSC frequencies was observed, while eMDSC levels remained stable. CONCLUSIONS: Our findings underscore the critical role of mMDSCs in HCC pathogenesis and their potential as a therapeutic target. The study also highlights the efficacy of mTACE in modulating the immunosuppressive tumor microenvironment, thereby opening new avenues for combinatorial immunotherapeutic strategies in HCC management.
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Células Supressoras Mieloides , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Células Supressoras Mieloides/imunologia , Quimioembolização Terapêutica/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Micropartículas Derivadas de Células/imunologia , Micropartículas Derivadas de Células/metabolismo , Adulto , Microambiente Tumoral/imunologiaRESUMO
OBJECTIVE: Hepatocellular carcinoma (HCC) poses a significant challenge to global health. Its pathophysiology involves interconnected processes, including cell proliferation, autophagy, and macrophage polarization. However, the role of Absent in Melanoma 2 (AIM2) in HCC remains elusive. METHODS: The expression of AIM2 in Huh-7 and Hep3B cell lines was manipulated and cell proliferation, autophagy, apoptosis, and migration/invasion, together with the polarization of M2 macrophages, were evaluated. The markers of autophagy pathway, LC3B, Beclin-1, and P62, underwent examination through Western blot analysis. An autophagy inhibitor, 3-MA, was used to measured the role of autophagy in HCC. Finally, the effect of AIM2 overexpression on HCC was further evaluated using a subcutaneous tumor model in nude mice. RESULTS: Our results established that AIM2 overexpression inhibits HCC cell proliferation, migration, and invasion while promoting apoptosis and autophagy. Conversely, knockdown of AIM2 engendered opposite effects. AIM2 overexpression was correlated with reduced M2 macrophage polarization. The autophagy inhibitor substantiated AIM2's role in autophagy and identified its downstream impact on cell proliferation, migration, invasion, and macrophage polarization. In the in vivo model, overexpression of AIM2 led to the inhibition of HCC tumor growth. CONCLUSION: The findings underscore AIM2's crucial function in modulating major biological processes in HCC, pointing to its potential as a therapeutic target. This study inaugurally demonstrated that AIM2 activates autophagy and influences macrophage polarization, playing a role in liver cancer progression.
Assuntos
Autofagia , Carcinoma Hepatocelular , Movimento Celular , Proliferação de Células , Neoplasias Hepáticas , Macrófagos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Autofagia/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Animais , Humanos , Camundongos , Macrófagos/metabolismo , Macrófagos/imunologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Apoptose/genética , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto , Ativação de Macrófagos/genéticaRESUMO
Inflammation plays a pivotal role in cancer development, with chronic inflammation promoting tumor progression and treatment resistance, whereas acute inflammatory responses contribute to protective anti-tumor immunity. Gasdermin D (GSDMD) mediates the release of pro-inflammatory cytokines such as IL-1ß. While the release of IL-1ß is directly linked to the progression of several types of cancers, the role of GSDMD in cancer is less clear. In this study, we show that GSDMD expression is upregulated in human breast, kidney, liver, and prostate cancer. Higher GSDMD expression correlated with increased survival in primary breast invasive carcinoma (BRCA), but not in liver hepatocellular carcinoma (LIHC). In BRCA, but not in LIHC, high GSDMD expression correlated with a myeloid cell signature associated with improved prognosis. To further investigate the role of GSDMD in anticancer immunity, we induced breast cancer and hepatoma tumors in GSDMD-deficient mice. Contrary to our expectations, GSDMD deficiency had no effect on tumor growth, immune cell infiltration, or cytokine expression in the tumor microenvironment, except for Cxcl10 upregulation in hepatoma tumors. In vitro and in vivo innate immune activation with TLR ligands, that prime inflammatory responses, revealed no significant difference between GSDMD-deficient and wild-type mice. These results suggest that the impact of GSDMD on anticancer immunity is dependent on the tumor type. They underscore the complex role of inflammatory pathways in cancer, emphasizing the need for further exploration into the multifaceted effects of GSDMD in various tumor microenvironments. As several pharmacological modulators of GSDMD are available, this may lead to novel strategies for combination therapy in cancer.
Assuntos
Neoplasias da Mama , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Ligação a Fosfato , Microambiente Tumoral , Animais , Proteínas de Ligação a Fosfato/metabolismo , Proteínas de Ligação a Fosfato/genética , Feminino , Humanos , Camundongos , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Microambiente Tumoral/imunologia , Camundongos Knockout , Modelos Animais de Doenças , Linhagem Celular Tumoral , Citocinas/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/genética , GasderminasRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) remains a formidable challenge in oncology, with its pathogenesis and progression influenced by myriad factors. Among them, the pervasive organic synthetic compound, bisphenol A (BPA), previously linked with various adverse health effects, has been speculated to play a role. This study endeavors to elucidate the complex interplay between BPA, the immune microenvironment of HCC, and the broader molecular landscape of this malignancy. METHODS: A comprehensive analysis was undertaken using data procured from both The Cancer Genome Atlas and the Comparative Toxicogenomics Database. Rigorous differential expression analyses were executed, supplemented by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. In addition, single-sample gene set enrichment analysis, gene set enrichment analysis and gene set variation analysis were employed to reveal potential molecular links and insights. Immune infiltration patterns were delineated, and a series of in vitro experiments on HCC cells were conducted to directly assess the impact of BPA exposure. RESULTS: Our findings unveiled a diverse array of active immune cells and functions within HCC. Distinct correlations emerged between high-immune-related scores, established markers of the tumor microenvironment and the expression of immune checkpoint genes. A significant discovery was the identification of key genes simultaneously associated with immune-related pathways and BPA exposure. Leveraging these genes, a prognostic model was crafted, offering predictive insights into HCC patient outcomes. Intriguingly, in vitro studies suggested that BPA exposure could promote proliferation in HCC cells. CONCLUSION: This research underscores the multifaceted nature of HCC's immune microenvironment and sheds light on BPA's potential modulatory effects therein. The constructed prognostic model, if validated further, could serve as a robust tool for risk stratification in HCC, potentially guiding therapeutic strategies. Furthermore, the implications of the findings for immunotherapy are profound, suggesting new avenues for enhancing treatment efficacy. As the battle against HCC continues, understanding of environmental modulators like BPA becomes increasingly pivotal.
Assuntos
Compostos Benzidrílicos , Carcinoma Hepatocelular , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , Fenóis , Microambiente Tumoral , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Compostos Benzidrílicos/efeitos adversos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Humanos , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Fenóis/efeitos adversos , Fenóis/toxicidade , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Biomarcadores Tumorais/genéticaRESUMO
Introduction: Precise staging and classification of liver fibrosis are crucial for the hierarchy management of patients. The roles of lactylation are newly found in the progression of liver fibrosis. This study is committed to investigating the signature genes with histone lactylation and their connection with immune infiltration among liver fibrosis with different phenotypes. Methods: Firstly, a total of 629 upregulated and 261 downregulated genes were screened out of 3 datasets of patients with liver fibrosis from the GEO database and functional analysis confirmed that these differentially expressed genes (DEGs) participated profoundly in fibrosis-related processes. After intersecting with previously reported lactylation-related genes, 12 DEGs related to histone lactylation were found and narrowed down to 6 core genes using R algorithms, namely S100A6, HMGN4, IFI16, LDHB, S100A4, and VIM. The core DEGs were incorporated into the Least absolute shrinkage and selection operator (LASSO) model to test their power to distinguish the fibrotic stage. Results: Advanced fibrosis presented a pattern of immune infiltration different from mild fibrosis, and the core DEGs were significantly correlated with immunocytes. Gene set and enrichment analysis (GSEA) results revealed that core DEGs were closely linked to immune response and chemokine signaling. Samples were classified into 3 clusters using the LASSO model, followed by gene set variation analysis (GSVA), which indicated that liver fibrosis can be divided into status featuring lipid metabolism reprogramming, immunity immersing, and intermediate of both. The regulatory networks of the core genes shared several transcription factors, and certain core DEGs also presented dysregulation in other liver fibrosis and idiopathic pulmonary fibrosis (IPF) cohorts, indicating that lactylation may exert comparable functions in various fibrotic pathology. Lastly, core DEGs also exhibited upregulation in HCC. Discussion: Lactylation extensively participates in the pathological progression and immune infiltration of fibrosis. Lactylation and related immune infiltration could be a worthy focus for the investigation of HCC developed from liver fibrosis.
Assuntos
Carcinoma Hepatocelular , Progressão da Doença , Cirrose Hepática , Neoplasias Hepáticas , Fenótipo , Humanos , Cirrose Hepática/patologia , Cirrose Hepática/genética , Cirrose Hepática/imunologia , Cirrose Hepática/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Perfilação da Expressão Gênica , Transcriptoma , Histonas/metabolismoRESUMO
CD98, also known as SLC3A2, is a multifunctional cell surface molecule consisting of amino acid transporters. CD98 is ubiquitously expressed in many types of tissues, but expressed at higher levels in cancerous tissues than in normal tissues. CD98 is also upregulated in most hepatocellular carcinoma (HCC) patients; however, the function of CD98 in HCC cells has been little studied. In this study, we generated a panel of monoclonal antibodies (MAbs) against surface proteins on human embryonic stem cells (hESCs). NPB15, one of the MAbs, bound to hESCs and various cancer cells, including HCC cells and non-small cell lung carcinoma (NSCLC) cells, but not to peripheral blood mononuclear cells (PBMCs) and primary hepatocytes. Immunoprecipitation and mass spectrometry identified the target antigen of NPB15 as CD98. CD98 depletion decreased cell proliferation, clonogenic survival, and migration and induced apoptosis in HCC cells. In addition, CD98 depletion decreased the expression of cancer stem cell (CSC) markers in HCC cells. In tumorsphere cultures, the expression of CD98 interacting with NPB15 was significantly increased, as were known CSC markers. After cell sorting by NPB15, cells with high expression of CD98 (CD98-high) showed higher clonogenic survival than cells with low expression of CD98 (CD98-low) in HCC cells, suggesting CD98 as a potential CSC marker on HCC cells. The chimeric version of NPB15 was able to induce antibody-dependent cellular cytotoxicity (ADCC) against HCC cells in vitro. NPB15 injection showed antitumor activity in an HCC xenograft mouse model. The results suggest that NPB15 may be developed as a therapeutic antibody for HCC patients.
Assuntos
Anticorpos Monoclonais , Carcinoma Hepatocelular , Proteína-1 Reguladora de Fusão , Neoplasias Hepáticas , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Animais , Camundongos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/imunologia , Proteína-1 Reguladora de Fusão/metabolismo , Proteína-1 Reguladora de Fusão/imunologia , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Embrionárias Humanas/imunologia , Proliferação de Células , Linhagem Celular Tumoral , Apoptose , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/imunologia , Cadeia Pesada da Proteína-1 Reguladora de FusãoRESUMO
BACKGROUND: Transcatheter arterial chemoembolization (TACE) combined with targeted therapy and immunotherapy can significantly improve the prognosis of patients with hepatocellular carcinoma (HCC). T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is a novel immunosuppressive molecule. This study aimed to analyze the clinical correlation between TIGIT expression on T cells and patients with HCC. METHODS: Clinical data from 140 patients with HCC were retrospectively collected, and TIGIT expression on T cells was examined in each patient. Patients were subsequently divided into high- and low-expression groups, and their prognosis was analyzed. RESULTS: Patients with a high TIGIT expression on their T cells at baseline had a larger tumor volume, later staging, higher proportion of regulatory T cells, higher blood concentrations of interleukin (IL)-6 and IL-10, and lower interferon-γ concentrations. Following TACE, CD155 concentration decreased; however, TACE did not affect TIGIT expression on T cells. Additionally, among patients receiving TACE combined with apatinib and camrelizumab treatment, patients with a high TIGIT expression on T cells had significantly shorter progression-free survival (PFS) and overall survival times than those of patients in the low-expression group. Patients receiving TACE combined with apatinib and camrelizumab treatment with higher TIGIT expression have shorter PFS time than those receiving TACE combined with apatinib treatment. CONCLUSIONS: Patients with HCC that have a high TIGIT expression on their T cells exhibited poorer baseline characteristics, immunosuppressive status, and prognosis after receiving TACE combined with apatinib and camrelizumab and maybe more suited to receive TACE combined with apatinib treatment instead.
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Receptores Imunológicos , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Masculino , Feminino , Prognóstico , Receptores Imunológicos/metabolismo , Pessoa de Meia-Idade , Estudos Retrospectivos , Quimioembolização Terapêutica/métodos , Idoso , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto , Receptores Virais/metabolismoRESUMO
Peritumoral hepatocytes are critical components of the liver cancer microenvironment, However, the role of peritumoral hepatocytes in the local tumor immune interface and the underlying molecular mechanisms have not been elucidated. YTHDF2, an RNA N6-methyladenosine (m6A) reader, is critical for liver tumor progression. The function and regulatory roles of YTHDF2 in peritumoral hepatocytes are unknown. This study demonstrated that oxaliplatin (OXA) upregulated m6A modification and YTHDF2 expression in hepatocytes. Studies using tumor-bearing liver-specific Ythdf2 knockout mice revealed that hepatocyte YTHDF2 suppresses liver tumor growth through CD8+ T cell recruitment and activation. Additionally, YTHDF2 mediated the response to immunotherapy. Mechanistically, OXA upregulated YTHDF2 expression by activating the cGAS-STING signaling pathway and consequently enhanced the therapeutic outcomes of immunotherapeutic interventions. Ythdf2 stabilized Cx3cl1 transcripts in an m6A-dependent manner, regulating the interplay between CD8+ T cells and the progression of liver malignancies. Thus, this study elucidated the novel role of hepatocyte YTHDF2, which promotes therapy-induced antitumor immune responses in the liver. The findings of this study provide valuable insights into the mechanism underlying the therapeutic benefits of targeting YTHDF2.
Assuntos
Linfócitos T CD8-Positivos , Quimiocina CX3CL1 , Hepatócitos , Neoplasias Hepáticas , Oxaliplatina , Proteínas de Ligação a RNA , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Animais , Quimiocina CX3CL1/metabolismo , Quimiocina CX3CL1/genética , Hepatócitos/metabolismo , Camundongos , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Humanos , Oxaliplatina/farmacologia , Microambiente Tumoral/imunologia , Camundongos Knockout , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Antineoplásicos/farmacologiaRESUMO
Background: Cancer-associated fibroblasts (CAFs) are the key components of the immune barrier in liver cancer. Therefore, gaining a deeper understanding of the heterogeneity and intercellular communication of CAFs holds utmost importance in boosting immunotherapy effectiveness and improving clinical outcomes. Methods: A comprehensive analysis by combing single-cell, bulk, and spatial transcriptome profiling with multiplexed immunofluorescence was conducted to unravel the complexities of CAFs in liver cancer. Results: Through an integrated approach involving 235 liver cancer scRNA-seq samples encompassing over 1.2 million cells, we found that CAFs were particularly increased in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). FAP + fibroblasts were identified as the dominant subtype of CAFs, and which were mainly involved in extracellular matrix organization and angiogenesis. These CAFs were enriched in the tumor boundary of HCC, but diffusely scattered within ICC. The DAB2 + and SPP1 + tumor-associated macrophages (TAMs) reinforce the function of FAP + CAFs through signals such as TGF-ß, PDGF, and ADM. Notably, the interaction between DAB2 + TAMs and FAP + CAFs promoted the formation of immune barrier and correlated with poorer patient survival, non-response to immunotherapy in HCC. High FAP and DAB2 immunohistochemical scores predicted shorter survival and higher serum AFP concentration in a local clinical cohort of 90 HCC patients. Furthermore, this communication pattern might be applicable to other solid malignancies as well. Conclusions: The interaction between DAB2 + TAMs and FAP + CAFs appears crucial in shaping the immune barrier. Strategies aimed at disrupting this communication or inhibiting the functions of FAP + CAFs could potentially enhance immunotherapy effectiveness and improve clinical outcomes.
Assuntos
Fibroblastos Associados a Câncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Microambiente Tumoral , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/imunologia , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/imunologia , Microambiente Tumoral/imunologia , Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Colangiocarcinoma/terapia , Colangiocarcinoma/patologia , Colangiocarcinoma/imunologia , Colangiocarcinoma/metabolismo , Imunoterapia/métodos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Masculino , Feminino , EndopeptidasesRESUMO
BACKGROUND: Hepatocellular carcinoma (LIHC) has severe consequences due to late diagnosis and the lack of effective therapies. Currently, potential biomarkers for the diagnosis and prognosis of LIHC have not been systematically evaluated. Previous studies have reported that RAC1 is associated with the B cell receptor signaling pathway in various tumor microenvironments, but its relationship with LIHC remains unclear. We investigated the relationship between RAC1 and the prognosis and immune infiltration microenvironment of LIHC, exploring its potential as a prognostic biomarker for this type of cancer. METHODS: In this study, we analyzed data from The Cancer Genome Atlas (TCGA) using the Wilcoxon signed-rank test and logistic regression to assess the association between RAC1 expression and clinical characteristics in LIHC patients. Additionally, Kaplan-Meier and Cox regression methods were employed to confirm the impact of RAC1 expression levels on overall survival. Immunohistochemistry was used to validate RAC1 protein expression in LIHC. We constructed RAC1 knockdown LIHC cells and studied the effects of RAC1 protein on cell proliferation and migration at both cellular and animal levels. RESULTS: RAC1 expression levels were significantly elevated in LIHC tissues compared to normal tissues. High RAC1 expression was strongly associated with advanced pathological stages and was identified as an independent factor negatively affecting overall survival. At both cellular and animal levels, RAC1 knockdown significantly inhibited the proliferation and migration of LIHC cells. Furthermore, RAC1 expression was positively correlated with the infiltration of Th2 cells and macrophages in the tumor microenvironment, suggesting that RAC1 may contribute to the deterioration of the tumor immunosuppressive microenvironment and potentially lead to reduced patient survival. CONCLUSION: These findings indicate that RAC1 expression promotes LIHC proliferation and migration and influences the landscape of immune cell infiltration in the tumor microenvironment. Based on these results, RAC1 is proposed as a potential prognostic biomarker for LIHC, associated with both cancer progression and tumor immune cell infiltration.
Assuntos
Biomarcadores Tumorais , Carcinoma Hepatocelular , Neoplasias Hepáticas , Microambiente Tumoral , Proteínas rac1 de Ligação ao GTP , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Humanos , Prognóstico , Masculino , Feminino , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Microambiente Tumoral/imunologia , Animais , Pessoa de Meia-Idade , Camundongos , Proliferação de Células , Movimento Celular , Linhagem Celular Tumoral , Linfócitos do Interstício Tumoral/imunologia , Camundongos NusRESUMO
Hepatocellular carcinoma (HCC) tissue is rich in dendritic cells, T cells, B cells, macrophages, natural killer cells and cellular stroma. Together they form the tumor microenvironment (TME), which is also rich in numerous cytokines. Tumorassociated macrophages (TAMs) are involved in the regulation of tumor development. TAMs in HCC receive stimuli in different directions, polarize in different directions and release different cytokines to regulate the development of HCC. TAMs are mostly divided into two cell phenotypes: M1 and M2. M1 TAMs secrete proinflammatory mediators, and M2 TAMs secrete a variety of antiinflammatory and protumorigenic substances. The TAM polarization in HCC tumors is M2. Both direct and indirect methods for TAMs to regulate the development of HCC are discussed. TAMs indirectly support HCC development by promoting peripheral angiogenesis and regulating the immune microenvironment of the TME. In terms of the direct regulation between TAMs and HCC cells, the present review mainly focuses on the molecular mechanism. TAMs are involved in both the proliferation and apoptosis of HCC cells to regulate the quantitative changes of HCC, and stimulate the related invasive migratory ability and cell stemness of HCC cells. The present review aims to identify immunotherapeutic options based on the mechanisms of TAMs in the TME of HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Microambiente Tumoral , Macrófagos Associados a Tumor , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Imunoterapia/métodosRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent malignancy with a high mortality rate worldwide. Suppressor of cytokine signaling (SOCS) family members play important roles in the proliferation, metabolism, and immunity of HCC cells by regulating cytokines and growth factors. However, it remains uncertain whether the level of SOCS family members can affect the prognosis of HCC patients. AIMS: This study aimed to comprehensively assess the role and mechanisms of SOCS family members in the development of HCC and to guide clinical selection. METHODS: We investigated the expression levels of SOCS family genes in HCC patients and their associations with various clinicopathological characteristics. We also utilized a public database to analyze the changes in the expression, potential functions, transcription factors, and immune invasion of SOCS family members. Additionally, we examined the prognostic value of the SOC family for HCC and its correlation with the SOC family and ferroptosis-related genes. RESULTS: This study revealed that the expression of SOCS2-7, and CISH was downregulated in HCC. The SOCS4, SOCS5, and SOCS7 genes were associated with the clinicopathological features of HCC patients. SOCS family genes are mainly related to the PIK3R3, GHR, and TNS4 pathways. Additionally, this study revealed that STAT3, PPAR-gamma 2, and IRF-2 are important transcription factors that regulate SOCS family members. The expression levels of SOCS family members are closely related to immune infiltration in liver cancer. The study also indicated that SOCS2 and SOCS4 are risk-related genes for predicting the prognosis of patients with liver cancer. Finally, this study suggested that the SOCS2 gene may be involved in the development and progression of HCC. CONCLUSION: Our study enhances the current understanding of SOCS gene function in liver cancer and can help clinicians select appropriate drugs and predict the prognosis of HCC patients.
Assuntos
Carcinoma Hepatocelular , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , Proteínas Supressoras da Sinalização de Citocina , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Proteínas Supressoras da Sinalização de Citocina/genética , Prognóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Masculino , Feminino , Ferroptose/genética , Pessoa de Meia-Idade , Perfilação da Expressão Gênica , MultiômicaRESUMO
Uveal melanoma (UM) is a rare melanoma originating in the eye's uvea, with 50% of patients experiencing metastasis predominantly in the liver. In contrast to cutaneous melanoma, there is only a limited effectiveness of combined immune checkpoint therapies, and half of patients with uveal melanoma metastases succumb to disease within 2 years. This study aimed to provide a path toward enhancing immunotherapy efficacy by identifying and functionally validating tumor-reactive T cells in liver metastases of patients with UM. We employed single-cell RNA-seq of biopsies and tumor-infiltrating lymphocytes (TILs) to identify potential tumor-reactive T cells. Patient-derived xenograft (PDX) models of UM metastases were created from patients, and tumor sphere cultures were generated from these models for co-culture with autologous or MART1-specific HLA-matched allogenic TILs. Activated T cells were subjected to TCR-seq, and the TCRs were matched to those found in single-cell sequencing data from biopsies, expanded TILs, and in livers or spleens of PDX models injected with TILs. Our findings revealed that tumor-reactive T cells resided not only among activated and exhausted subsets of T cells, but also in a subset of cytotoxic effector cells. In conclusion, combining single-cell sequencing and functional analysis provides valuable insights into which T cells in UM may be useful for cell therapy amplification and marker selection.
Assuntos
Linfócitos do Interstício Tumoral , Melanoma , Análise de Célula Única , Neoplasias Uveais , Neoplasias Uveais/imunologia , Neoplasias Uveais/patologia , Neoplasias Uveais/genética , Humanos , Melanoma/imunologia , Melanoma/patologia , Melanoma/secundário , Melanoma/genética , Linfócitos do Interstício Tumoral/imunologia , Animais , Camundongos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/genética , Feminino , Masculino , XenoenxertosRESUMO
Introduction: This study aims to use machine learning to conduct in-depth analysis of key factors affecting the recurrence of HCC patients with high preoperative systemic immune-inflammation index (SII) levels after receiving ablation treatment, and based on this, construct a nomogram model for predicting recurrence-free survival (RFS) of patients. Methods: This study included clinical data of 505 HCC patients who underwent ablation therapy at Beijing You'an Hospital from January 2014 to January 2020, and accepted 65 HCC patients with high SII levels from Beijing Ditan Hospital as an external validation cohort. 505 patients from Beijing You'an Hospital were divided into low SII and high SII groups based on the optimal cutoff value of SII scores. The high SII group was further randomly divided into training and validation cohorts in a 7:3 ratio. eXtreme Gradient Boosting (XGBoost), random survival forest (RSF), and multivariate Cox regression analysis, were used to explore the factors affecting the post-ablation RFS of HCC patients. Based on the identified key factors, a nomogram model were developed to predict RFS in HCC patients, and their performance were evaluated using the concordance index (C index), receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA). The optimal cutoff value for nomogram scores was used to divide patients into low- and high-risk groups, and the effectiveness of the model in risk stratification was evaluated using Kaplan-Meier (KM) survival curves. Results: This study confirmed that age, BCLC stage, tumor number, and GGT level were independent risk factors affecting RFS in HCC patients. Based on the selected risk factors, an RFS nomogram was successfully constructed. The C-index, ROC curve, calibration curve, and DCA curve each demonstrated the discrimination, accuracy, and decision-making utility of the nomogram, indicating that it has good predictive performance. KM curve revealed the nomogram could significantly differentiate patient populations with different recurrence risk. Conclusion: We developed a reliable nomogram that can accurately predict the 1-, 3-, and 5-year RFS for HCC patients with high SII levels following ablation therapy.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Aprendizado de Máquina , Recidiva Local de Neoplasia , Nomogramas , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/diagnóstico , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Prognóstico , Inflamação/imunologia , Idoso , Fatores de Risco , AdultoRESUMO
Integrating immunotherapy with natural compounds holds promise in enhancing the immune system's ability to eliminate cancer cells. Cordyceps militaris, a traditional Chinese medicine, emerges as a promising candidate in this regard. This study investigates the effects of cordycepin and C. militaris ethanolic extract (Cm-EE) on sensitizing cancer cells and regulating immune responses against breast cancer (BC) and hepatocellular carcinoma (HCC) cells. Cordycepin, pentostatin and adenosine were identified in Cm-EE. Cordycepin treatment decreased HLA-ABC-positive cells in pre-treated cancer cells, while Cm-EE increased NKG2D ligand and death receptor expression. Additionally, cordycepin enhanced NKG2D receptor and death ligand expression on CD3-negative effector immune cells, particularly on natural killer (NK) cells, while Cm-EE pre-treatment stimulated IL-2, IL-6, and IL-10 production. Co-culturing cancer cells with effector immune cells during cordycepin or Cm-EE incubation resulted in elevated cancer cell death. These findings highlight the potential of cordycepin and Cm-EE in improving the efficacy of cancer immunotherapy for BC and HCC.
Assuntos
Cordyceps , Desoxiadenosinas , Imunoterapia , Humanos , Desoxiadenosinas/farmacologia , Cordyceps/química , Imunoterapia/métodos , Linhagem Celular Tumoral , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/terapia , Feminino , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias da Mama/imunologia , Neoplasias da Mama/tratamento farmacológicoRESUMO
Chimeric antigen receptor-engineered T (CAR-T) cell therapy of cancer has been a hotspot and promising. However, due to rapid exhaustion, CAR-T cells are less effective in solid tumors than in hematological ones. CD122+CXCR3+ memory T cells are characterized with longevity, self-renewal and great antitumoral capacity. Thus, it's compelling to induce memory CAR-T cells to enhance their efficacy on solid tumors. Astragalus polysaccharide (APS) has reportedly exhibited antitumoral effects. However, it's unclear if APS has an impact on CD8+ memory T cell generation or persistence. Using two human cancer cell lines, here we found that APS significantly improved the persistence of GPC3-targeted CAR-T cells and enhanced their suppression of tumor growth in both Huh7 and HepG2 xenograft models of hepatocellular carcinoma. APS increased CD122+/CXCR3+ memory T cells, but decreased their PD-1+ subset within CD8+ CAR-T cells in tumor-bearing mice, while these effects of APS were also confirmed with in vitro experiments. Moreover, APS augmented the expression of chemokines CXCL9/CXCL10 by the tumor in vivo and in vitro. It also enhanced the proliferation and chemotaxis/migration of CAR-T cells in vitro. Finally, APS promoted the phosphorylation of STAT5 in CD8+ CAR-T cells, whereas inhibition of STAT5 activation reversed these in vitro effects of APS. Therefore, APS enhanced the antitumoral effects of CD8+ CAR-T cells by promoting formation/persistence of CD122+/CXCR3+/PD-1- memory T cells and their migration to the tumor.