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Project description:Hepatocellular carcinoma (HCC) is one of the most lethal cancers for humans. HCC is highly heterogeneous. In this study, we performed ultra-depth (~1 million reads per spot) spatial sequencing on a case of HCC. Sixteen distinct spatial expression clusters were identified. Each of these clusters was spatially contiguous and had distinct gene expression patterns. In contrast, benign liver tissues showed minimal heterogeneity in terms of gene expression. Numerous immune cell-enriched spots were identified in both HCC and benign liver regions. Cells adjacent to these immune cell-enriched spots showed significant alterations in their gene expression patterns. Interestingly, the responses of HCC cells to the nearby immune cells were significantly more intense and broader, while the responses of benign liver cells to immune cells were somewhat narrow and muted, suggesting an innate difference in immune cell activities towards HCC cells in comparison with benign liver cells. When standard-depth sequencing was performed, significant numbers of genes and pathways that were associated with these changes disappeared. Qualitative differences in some pathways were also found. These results suggest that deep spatial sequencing may help to uncover previously unidentified mechanisms of liver cancer development.
2025-04-16 | GSE283405 | GEO
Project description:Hepatocellular carcinoma (HCC) is one of the most lethal cancers for humans. HCC is highly heterogeneous. In this study, we performed ultra-depth (~1 million reads per spot) spatial sequencing on a case of HCC. Sixteen distinct spatial expression clusters were identified. Each of these clusters was spatially contiguous and had distinct gene expression patterns. In contrast, benign liver tissues showed minimal heterogeneity in terms of gene expression. Numerous immune cell-enriched spots were identified in both HCC and benign liver regions. Cells adjacent to these immune cell-enriched spots showed significant alterations in their gene expression patterns. Interestingly, the responses of HCC cells to the nearby immune cells were significantly more intense and broader, while the responses of benign liver cells to immune cells were somewhat narrow and muted, suggesting an innate difference in immune cell activities towards HCC cells in comparison with benign liver cells. When standard-depth sequencing was performed, significant numbers of genes and pathways that were associated with these changes disappeared. Qualitative differences in some pathways were also found. These results suggest that deep spatial sequencing may help to uncover previously unidentified mechanisms of liver cancer development.
2025-04-16 | GSE283404 | GEO
Project description:Deep Spatial Sequencing Revealing Differential Immune Responses in Human Hepatocellular Carcinoma
| PRJNA1193588 | ENA
Project description:Deep Spatial Sequencing Revealing Differential Immune Responses in Human Hepatocellular Carcinoma [AVITI]
| PRJNA1193594 | ENA
Project description:Deep Spatial Sequencing Revealing Differential Immune Responses in Human Hepatocellular Carcinoma [NextSeq]
| PRJNA1193592 | ENA
Project description:Infiltrating immune cells in the tumor microenvironment (TME) influence tumor progression and patient prognosis, making them attractive therapeutic targets for immunotherapy research. A deeper understanding of immune cell distributions in the TME in hepatocellular carcinoma (HCC) is needed to identify interactions among different immune cell types that might impact the effectiveness of potential immunotherapies. We performed multiplex immunohistochemistry using a tissue microarray of samples from 302 patients with HCC to elucidate the spatial distributions of immune cell subpopulations (CD3+ , CD4+ , CD8+ , CD66b+ , and CD68+ ) in HCC and normal liver tissues. We analyzed the associations between different immune subpopulations using Pearson's correlation. G(r) functions, K(r) functions and Euclidean distance were applied to characterize the bivariate distribution patterns among the immune cell types. Cox regression and Kaplan-Meier analysis were used to evaluate the associations between tumor infiltration by different immune cells and patient outcomes after curative surgery. We also analyzed the relationship between the spatial distribution of different immune cell subpopulations with HCC patient prognosis. We found that the immune cell spatial distribution in the HCC TME is heterogeneous. Our study provides a theoretical basis for HCC immunotherapy.
| S-EPMC8819352 | biostudies-literature
Project description:Rationale: Hepatocellular carcinoma (HCC) is a highly heterogeneous and malignant disease with the complex immune microenvironment, which ultimately influence clinic outcomes of patients. However, the spatial expression patterns of diverse immune cells among tumor microenvironment remain to be further deciphered. Methods: Spatial transcriptomics sequencing (ST) was implemented on two portions of HCC specimens. Differentially expressed genes, cell cycle phases, epithelial-mesenchymal features, pseudo-time and immune infiltration analysis were applied to demonstrate the intratumor heterogeneity and define the specific immune-related regions, and the results were further validated by a second analysis on another ST study. In vitro and in vivo experiments were conducted to confirm the functional mechanisms of key molecules such as CCL15, CCL19 and CCL21. Clinical tissue samples were used to assess their potential prognostic and therapeutic values. Results: Totally, 7553 spots were categorized into 15 subsets by hierarchical clustering, and malignant subsets with intratumor heterogeneity phenotypes were identified. Spatial heterogeneity from distinct sectors highlights specific chemokines: CCL15 is remarkable in the core region of the carcinoma sector and facilitates the immunosuppressive microenvironment by recruiting and polarizing M2-like macrophages in vitro and in vivo; High expression of CCL15 and CD163 respectively predicts poor prognosis of HCC patients, and the combined application of them has better predictive value. CCL19 and CCL21, sharing similar spatial expression patterns, are highly-correlated and prominent in the immune infiltration enrichment and recruit CD3+ T cells and CD20+ B cells to inhibit the growth of HCC, indicating a good prognosis of HCC patients. Conclusions: Taken together, our studies preliminarily reveal intratumor heterogeneity of HCC based on ST techniques and unravel the previously unexplored spatial expression patterns in the immune microenvironment. We also highlight the clinical significance and spatial discrepancy of key molecules, providing novel insight for further developing therapeutic strategies in HCC.
| S-EPMC9169356 | biostudies-literature
Project description:The purpose of this experiment of high-coverage DNA sequencing of 58 frequently mutated genes in hepatocellular carcinoma (HCC) is to confirm clonal distribution of the known HCC drivers in samples corresponding to multiple regions of a tumor.
2020-01-16 | E-MTAB-5899 | biostudies-arrayexpress
Project description:Background and aimsImmune checkpoint inhibitors (ICIs) exhibit significant clinical activity in patients with advanced hepatocellular carcinoma (HCC). This study explored whether tumor response to ICIs in HCC varies among different organs.MethodsWe reviewed the data of patients with advanced HCC who had received ICIs. Patients with measurable diseases were enrolled. Organ-specific response criteria, adapted from RECIST 1.1 and immune-related RECIST, were used to evaluate the objective response to ICIs in tumors located in the liver, lung, lymph node, and other intra-abdominal sites.ResultsOf the 75 enrolled patients with advanced HCC, 51 and 11 patients had chronic hepatitis B virus and chronic hepatitis C virus infection, respectively. Regarding ICI treatment, 58, 1, and 16 patients had undergone anti-PD-1/anti-PD-L1 monoclonal antibody (mAb) alone, anti-CTLA4 mAb alone, and anti-PD-1 mAb plus anti-CTLA4 mAb, respectively; 20 and 55 patients had received ICIs as first-line or ≥second-line therapy. The overall objective response rate (ORR) was 28.0%. In total, 58, 34, 19, and 18 patients had measurable hepatic tumors and lung, lymph node, and other intra-abdominal metastases, and the corresponding organ-specific ORRs were 22.4, 41.2, 26.3, and 38.9%, respectively. Of the 39 patients who had both hepatic and extrahepatic tumors, 12 had disease control in extrahepatic tumors while progressive disease (PD) in hepatic tumors, whereas only 4 exhibited disease control in hepatic tumors while PD in extrahepatic tumors (p = 0.046, McNemar test). Of the 16 patients with only evaluable tumors in the liver and lungs at baseline, 8 had disease control in the lungs while PD in the liver, and none experienced disease control in the liver while PD in the lungs (p = 0.005).ConclusionsThe hepatic tumors of HCC may be less responsive to ICIs than extrahepatic lesions. Lung metastases responded most favorably to ICIs. The mechanisms underlying this differential response to ICIs warrant further investigation.
| S-EPMC6883443 | biostudies-literature
Project description:MicroRNAs (miRNAs/miRs), consisting of ~22 nucleotides of single-stranded RNA, participate in post-transcriptional gene regulation by binding to the 3'-untranslated region (UTR) of mRNAs, repressing their translation and promoting their degradation. Studies have shown that certain miRNAs play a key role in the control of various cellular activities, such as inhibiting inflammation, modulating cell differentiation and suppressing cancer growth. The role of miR-146a in the immune response and in the pathogenesis of hepatocellular carcinoma (HCC) has also been investigated. Although some studies have shown that increased miR-146a levels are associated with HCC, others have revealed that miR-146a suppresses cancer cell proliferation, invasion and metastasis. Toll-like receptor 4 (TLR4) signaling has an important role in regulating innate and adaptive immune responses. In addition, TLR4 is functionally expressed in HCC cells and promotes HCC cell proliferation, which can be regulated by miR-146a. The present review focuses on the recent progress in analyzing the multiple roles of miR-146a in mediating the TLR4 pathway and adaptive immune response. Finally, the function of miR-146a in the pathogenesis of HCC is also discussed.
| S-EPMC6781720 | biostudies-literature