Camrelizumab-targeting a novel PD-1 epitope to treat hepatocellular carcinoma.
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ABSTRACT:
SUBMITTER: Rakke YS
PROVIDER: S-EPMC7791240 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
Publications
Camrelizumab-targeting a novel PD-1 epitope to treat hepatocellular carcinoma.
Rakké Yannick Sebastiaan YS Sprengers Dave D Kwekkeboom Jaap J IJzermans Jan Nicolaas Maria JNM
Annals of translational medicine 20201201 23
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Project description:[This corrects the article DOI: 10.1155/2017/6238106.].
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Project description:As the leading cause of cancer-related death, hepatocellular carcinoma (HCC) threatens human health and limited treatments are available to cure the disease efficiently and effectively. The particularly immunotolerant environment of the liver lowers the efficacy of current therapies in patients with advanced HCC. Traditional Chinese medicine (TCM) is gathering increasing interest due to the immunoregulatory properties of certain compounds. In advanced HCC, TCM can restore immunosurveillance to promote antitumor effects in several ways, including the upregulation of immunostimulatory factors and the downregulation of immunosuppressive factors. The characteristic multitarget regulation of TCM compounds may provide new insights regarding effective HCC immunotherapies. Here, we review the immunoregulatory potency of TCMs for treating HCC and explain how individual TCM drugs and complex formulas remodel the immune environment in various cell- and cytokine-dependent manners.
| S-EPMC7305542 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-01-29 | GSE196393 | GEO
Project description:Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells (APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma (HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from non-cancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.
| S-EPMC5937202 | biostudies-literature
Project description:Methods83 patients with hepatocellular carcinoma (HCC) admitted to the interventional oncology department were randomly divided into two groups. Apatinib and camrelizumab were administered to 42 patients in group A, whereas sorafenib was administered to 41 patients in group B for three months. The clinical efficacy was evaluated in terms of objective response rate (ORR), and disease control rate (DCR). Certain tumor markers like alpha-fetoprotein (AFP), carbohydrate antigen 199 (CA199), carcinoembryonic antigen (CEA), hypoxia-inducible factor (HIF-1), immune function T lymphocyte subsets (CD3+, CD4+, CD8+, CD4+/CD8+) were determined before and after treatment. The serum levels of vascular endothelial growth factor (VEGF), osteopontin (OPN), aspartate aminotransferase (AST), and epidermal growth factor 7 (EGF7)] were observed. The survival time between the two groups was compared, such as progression-free survival (PFS) and median survival (MS). Finally, the toxicity and side effects data were also obtained.ResultsThe ORR and DCR of group A were 69.05% and 88.10%, respectively, which were significantly higher (P<0.05) than group B (ORR=53.66% and DCR=70.73%). After treatment, the AFP, CA199, CEA, and HIF-1 levels of both groups decreased significantly (P<0.05), and the respective biomarker levels of group A were lower than those of group B (P<0.05). Following treatment, CD3+, CD4+, CD4+/CD8+ index in group A significantly increased (P<0.05) while CD8+ level was significantly decreased (P<0.05). Compared to group B, a significant increase was observed in group A's CD3+, CD4+, and CD4+/CD8+ index. There were no significant changes in CD3+, CD4+, CD8+, CD4+/CD8+ indexes before and after treatment in group B (P>0.05). The serum level of VEGF, OPN, EGF-7 and AST indexes of group A&B were decreased significantly (P<0.05). Compared with group B, the VEGF, OPN, EGF7 and AST indexes of group A were significantly reduced (P<0.05). PFS and MS in group A were significantly higher than in group B (P<0.05). There was no significant difference between groups A and B in terms of toxicity and adverse effects (P>0.05).ConclusionIn treating HCC, combining apatinib and camrelizumab can reduce tumor markers, enhance the immune system and curative effect, and prolong patient survival. The underline mechanism is related to the down-regulation of VEGF, OPN and HIF-1 indexes.
| S-EPMC10090460 | biostudies-literature
Project description:Abstract: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Despite new treatment approvals, treatment response and prognosis of patients with advanced HCC remains poor. Claudin-1 (CLDN1) is a membrane protein expressed in tight junctions but also non-junctionally at the basolateral membrane of hepatocytes. While the function of CLDN1 within tight junctions is well characterized, the role of non-junctional (NJ) CLDN1 in HCC remains unexplored. Here we show that targeting NJ-CLDN1 with a humanized monoclonal antibody (mAb) suppresses tumor growth in different pre-clinical models. Mechanistic studies including single cell RNA sequencing of multicellular patient tumorspheres suggest that non-junctional CLDN1 regulates tumor stemness, metabolism and oncogenic signaling with impact on the tumor immune microenvironment. Our results provide the rationale for targeting NJ-CLDN1 in HCC and pave the way to novel therapeutic interventions with NJ-CLDN1 mAbs aimed at improving the limited efficacy of current therapies.
2025-01-29 | GSE196390 | GEO
Project description:Abstract: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Despite new treatment approvals, treatment response and prognosis of patients with advanced HCC remains poor. Claudin-1 (CLDN1) is a membrane protein expressed in tight junctions but also non-junctionally at the basolateral membrane of hepatocytes. While the function of CLDN1 within tight junctions is well characterized, the role of non-junctional (NJ) CLDN1 in HCC remains unexplored. Here we show that targeting NJ-CLDN1 with a humanized monoclonal antibody (mAb) suppresses tumor growth in different pre-clinical models. Mechanistic studies including single cell RNA sequencing of multicellular patient tumorspheres suggest that non-junctional CLDN1 regulates tumor stemness, metabolism and oncogenic signaling with impact on the tumor immune microenvironment. Our results provide the rationale for targeting NJ-CLDN1 in HCC and pave the way to novel therapeutic interventions with NJ-CLDN1 mAbs aimed at improving the limited efficacy of current therapies.
2025-01-29 | GSE196392 | GEO
Project description:Hepatocelluar carcinoma (HCC) is the most lethal cancer in the world. Most HCC over-express c-Myc, which plays a critical role in regulating cellular growth, differentiation and apoptosis in both normal and neoplastic cells. c-Myc is among the most frequently overexpressed genes in human cancers. Overexpression of c-Myc in hepatic cells leads to development of hepatocellular carcinoma. Here, we review the current progress in understanding physiologic function and regulation of c-Myc as well as its role in hepatic carcinogenesis and discuss the association of c-Myc activation in chronic hepatitis B infection and the upregulation of HIF-1/VEGF. We also explore the possibility of treating HCC by inhibiting c-Myc and examine the pros and cons of such an approach. Although this strategy is currently not available in clinics, with recent advances in better drug design, pharmacokinetics and pharmacogenetics, inhibition of c-Myc might become a novel therapy for HCC in the future.
| S-EPMC2999263 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) has a high morbidity and mortality rate worldwide, with limited treatment options. Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored glycoprotein that is overexpressed in most HCC tissues but not in normal tissues. GPC3-targeting antibody therapy shows limited response in a clinical trial due to the lack of a tumor-specific cytotoxic T lymphocyte (CTL) response. Here, in C57/B6 mice, we demonstrated that intravenous infusion of GPC3-coupled lymphocytes (LC/GPC3+) elicited robust GPC3-specific antibody and CTL responses, which effectively restricted proliferation and lysed cultured-HCC cells. Treatment with LC/GPC3+ induced durable tumor regression in HCC-bearing C57/B6 mice. Administration of LC/GPC3+ induced elevated levels of the cytotoxic T cell bioactive factors tumor necrosis factor alpha (TNF-?), interferon-? (IFN-?), granzyme B, and perforin, and substantially increased the number of infiltrating CD8+ T cells in tumor tissues. Moreover, immune responses elicited by LC/GPC3+ selectively suppressed GPC3+ tumors, but didn't affect the GPC3- tumors in BALB/c mice. Our findings provide the first preclinical evidence that intravenous infusion of the LC/GPC3+ complex can induce a strong anti-HCC effect through regulating systemic and local immune responses. These results indicate that the LC/GPC3+ complex could be developed as precision therapeutics for HCC patients in the future.
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Project description:Molecule-targeted therapy, such as sorafenib, is one of the effectively therapeutic options for advanced hepatocellular carcinoma (HCC). However, acquired resistance to sorafenib has been found in some HCC patients, resulting in poor prognosis. It is reported that PD-L1 and DNA methyltransferases (DNMTs) contribute to drug resistance. In this study, by inducing sorafenib-resistant HCC cell lines, we investigated their molecular and functional characteristics. Our data indicated that highly upregulated DNMT1 was positively correlated with PD-L1 overexpression in sorafenib-resistant HCC cells. We demonstrate that PD-L1 regulate DNMT1 through STAT3 signaling pathway. Knockdown of PD-L1 induced DNMT1-dependent DNA hypomethylation and restored the expression of methylation-silenced CDH1. Moreover, inactivation of NFκB blocked PD-L1/STAT3/DNMT1 pathway in sorafenib-resistant HCC cells. Functionally, genetic or pharmacological disruption of PD-L1 or/and DNMT1 sensitize HCC resistance to sorafenib. Importantly, dual inactivation of PD-L1 and DNMT1 by their inhibitor synergistically disrupts the colony formation of sorafenib-resistant HCC cells. These results demonstrate that targeting NFκB/PDL1/STAT3/DNMT1 axis is a new therapeutic strategy for preventing or overcoming the acquired resistance to sorafenib in HCC patients.
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