Anti-PD1 monotherapy in hepatocellular carcinoma: a step forward or already behind?
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ABSTRACT:
SUBMITTER: Catanese S
PROVIDER: S-EPMC7812228 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundGLI-similar 1 (GLIS1) is one of of Krüppel-like zinc finger proteins, which are either stimulators or inhibitors of genetic transcription. Nevertheless, its effects on T cell were elusive.MethodsIn this study, we intend to explore the effects of GLIS1 on modulating the anticancer potency of CD8+ T cells in hepatocellular carcinoma (HCC). The expression of GLIS1 in CD8 peripheral blood mononuclear cell and CD8 tumor-infiltrating lymphocytes of HCC tissues was validated by quantificational real-time-PCR and flow cytometry. The anticancer potency of CD8+ T cells with GLIS1 knock down was confirmed in C57BL/6 mouse model and HCC patient-derived xenograft mice model. GLIS1-/- C57BL/6 mice was applied to explore the effects GLIS1 on tumor immune microenvironment. Chromatin immunoprecipitation and RNA transcriptome sequencing analysis were both performed in GLIS1-knock down of CD8+ T cells.ResultsGLIS1 was upregulated in exhausted CD8+ T cells in HCC. GLIS1 downregulation in CD8+ T cells repressed cancer development, elevated the infiltrate ability of CD8+ T cells, mitigated CD8+ T cell exhaustion and ameliorated the anti-PD1 reaction of CD8+ T cells in HCC. The causal link beneath this included transcriptional regulation of SGK1-STAT3-PD1 pathway by GLIS1, thereby maintaining the abundant PD1 expression on the surface of CD8+ T cells.ConclusionOur study revealed that GLIS1 promoted CD8+ T cell exhaustion in HCC through transcriptional regulating SGK1-STAT3-PD1 pathway. Downregulating the expression of GLIS1 in CD8+ T cells exerted an effect with anti-PD1 treatment synergistically, revealing a prospective method for HCC immune therapy.
| S-EPMC9930610 | biostudies-literature
Project description:PurposeAnti-programmed cell death protein 1 (PD1)±anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint inhibitors (ICIs) are standard therapeutic options for metastatic melanoma. We assessed whether biologic subtype according to primary tumor type or genomic subtype can function as predictive biomarkers for anti-PD1±anti-CTLA4 ICI in patients with advanced melanoma.MethodsWe performed a single-center retrospective cohort analysis of patients who received anti-PD1±anti-CTLA4 ICI for advanced melanoma between 2012 and 2019. Primary tumor type, BRAF and NRAS mutation status, and other covariates were abstracted from chart review. Log-rank tests and multivariable Cox regression models were used to assess differences in clinical progression-free (cPFS) and overall survival (OS).ResultsWe identified 230 patients who received 249 lines of anti-PD1±anti-CTLA4 ICI for unresectable or metastatic disease. Of these patients, 74% were cutaneous, 11% mucosal, 8% unknown primary and 7% acral. BRAF and NRAS mutations were identified in 35% and 28% of patients, respectively. In multivariable analyses of the entire cohort, acral or mucosal primary tumor type, >3 metastatic sites, elevated LDH were predictive of shorter cPFS and OS. Combination ICI therapy was associated with longer cPFS (HR 0.57, 95% CI 0.38 to 0.86, p=0.007) and OS (HR 0.42, 95% CI 0.28 to 0.65, p<0.001). Combination ICI was significantly associated with longer OS in unknown primary and mucosal melanoma. There was a non-significant trend toward longer OS with anti-PD1+anti-CTLA4 in cutaneous melanoma, but not in acral melanoma. In multivariable analyses, combination ICI was associated with longer OS in NRAS (HR 0.24, 95% CI 0.10 to 0.62, p=0.003, n=69) and BRAF V600E/K (HR 0.47, 95% CI 0.24 to 0.90, p=0.024, n=86) mutant melanoma but not BRAF/NRAS wild-type (n=94) melanoma.ConclusionsIn our cohort, primary melanoma tumor type and genomic subtype were independent predictive markers of cPFS and OS for patients with metastatic melanoma receiving anti-PD1 ICI. Primary tumor type and genomic subtype-including NRAS-should be further evaluated in prospective clinical trials to determine their value as predictive markers. Biologic subtypes may facilitate clinical decision-making when recommending combination ICI treatment (anti-PD1±anti-CTLA4) versus anti-PD1 alone for patients with metastatic melanoma.
| S-EPMC7831745 | biostudies-literature
Project description:Anti-PD-1/PD-L1 immunotherapy has limited efficacy in hepatocellular carcinoma (HCC) and does not benefit all patients. A FAK inhibitor (VS-4718) has been reported to improve the microenvironment in some tumors. This study aimed to investigate the effect of the combination of the FAK inhibitor VS4718 and anti-PD1 for the treatment of HCC in a mouse model and its possible mechanism of action. The expression of FAK and infiltrated immune cells in human HCC from the data of TCGA were analyzed. A primary murine HCC model was established via protooncogene (c-Met/β-catenin) transfection. The pathological characteristics of tumors were examined after the mice were treated with VS4718 and/or anti-PD1 therapy. This study revealed that FAK is highly expressed in human HCC and is associated with poor prognosis of OS (overall survival) and PFS (progress free survival) in HCC patients. Immune cell infiltration (CD8+ T, Tregs, M0, M2, CAFs and MDSCs) was correlated with FAK expression. In the experimental HCC model, the combination of a FAK inhibitor VS4718 and an anti-PD1 antibody had a better effect than monotherapy against HCC. VS4718 reduced the number of Tregs and macrophages but increased the number of CD8+ T cells in HCC mice. Notably, FAK inhibitor promoted the expression of PD-L1 in HCC. This study suggested that combination of the FAK inhibitor VS4718 and anti-PD1 could be a potential therapy for HCC by improving the immune environment, reducing liver fibrosis and simultaneously preventing PD1 from binding to the increased PD-L1 induced by FAK inhibitor VS4718.
| S-EPMC8804348 | biostudies-literature
Project description:Immunotherapy treatments, particularly immune checkpoint blockade, can result in benefits in clinical settings. But many pre-clinical and clinical studies have shown that resistance to anti-PD1 therapy frequently occurs, leading to tumor recurrence and treatment failure, including in patients with hepatocellular carcinoma (HCC). In this study, 10 patients with HCC were remedied with anti-PD1, and pre-treatment biopsy samples were sequenced for 289 nanostring panel RNA to compare responsive and non-responsive tumors to identify possible pretreatment biomarkers or targets of anti-PD1 therapeutic responses. Fortunately, the expression of β-Glucuronidase (GUSB) in the non-responding tumors was found to be remarkably higher than that in responding tumors. Results of the cell counting kit 8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), transwell, wound healing test, and flow cytometry showed that GUSB facilitated proliferation, invasion, as well as migration of human HCC cells and downregulated PD-L1 expression by promoting miR-513a-5p. Additionally, as a GUSB inhibitor, amoxapine can reduce the progression of human HCC cells, and was an effective treatment for HCC and improved the sensitivity of anti-PD1 therapy. In summary, this study reveals that increased GUSB downregulates PD-L1 expression by promoting miR-513a-5p, leading to primary resistance to anti-PD1 treatment in HCC, and amoxapine enhances the sensitivity of anti-PD1 therapy by inhibiting GUSB, providing a new strategy and method for improving the efficacy of anti-PD1 therapy and bringing new prospects for therapy of HCC.
| S-EPMC9257027 | biostudies-literature
Project description:Anti-Programmed cell Death protein 1 (Anti-PD1) or Programmed Death-Ligand 1 (PDL1) immune checkpoint inhibitors provide treatment options for advanced HCC patients with low response rates. Combination therapy is becoming a major issue to improve the unmet need. Proton beam radiotherapy (PBT) could effectively control the local tumor with a low-risk injury to peripheral liver parenchyma. We retrospectively reviewed the patients who have received PBT combined with anti-PD1/PDL1 to evaluate the efficacy and safety of the advanced HCC patients. This study reviewed 29 advanced HCC patients who have received PBT and anti-PD1/PDL1 during 2016 and 2019. All were Child-Pugh A and performance status 0-1. Seventeen patients (58.6%) had extrahepatic spreading. Concurrent PBT started during anti-PD1/PDL1 with a median of 96.6 grays equivalent dose. The PBT field covered all tumors in 13 (44.8%) patients under curative intent. Other patients (55.2%) received palliative PBT that covered only the principal tumors. All patients have completed the concurrent PBT protocol. The median anti-PD1/PDL1 duration was 3.9 months. After a median follow-up of 13.2 months, the rates of 1-year PBT infield tumor control, 1-year outfield tumor control, and overall response were 90.5%, 90.9%, and 61.5%, and 70.8%, 69.2%, and 43.8%, respectively for curative-intent and palliative-control PBT. Complete response was found in 4 (30.8%) curative-intent and 1 (6.3%) palliative-control patients. The median overall progression-free survival was 27.2 months for curative-intent patients and 15.9 months for palliative-control patients. The overall survival was non-reached for both groups. The ALBI grade and Child-Pugh score change at 3-month and 6-month after PBT initiation were nonsignificant. No unexpected adverse event occurred except nine patients (31.0%) had treatment-related adverse events higher than or equal to Grade 3, including 2 (6.9%) had a radiation-induced liver injury. PBT combined with anti-PD1/PDL1 was safe without unexpected adverse events. The concurrent therapy could effectively treat advanced HCC through sustained local tumor necrosis and effective systemic tumor control for the patients who received curative-intent or palliative-control PBT combined with anti-PD1/PDL1.
| S-EPMC9077059 | biostudies-literature
Project description:BackgroundCircular RNAs (circRNAs) can be encapsulated into exosomes to participate in intercellular communication, affecting the malignant progression of a variety of tumors. Dysfunction of CD8 + T cells is the main factor in immune escape from hepatocellular carcinoma (HCC). Nevertheless, the effect of exosome-derived circRNAs on CD8 + T-cell dysfunction needs further exploration.MethodsThe effect of circCCAR1 on the tumorigenesis and metastasis of HCC was assessed by in vitro and in vivo functional experiments. The function of circCCAR1 in CD8 + T-cell dysfunction was measured by enzyme-linked immunosorbent assay (ELISA), western blotting and flow cytometry. Chromatin immunoprecipitation, biotinylated RNA pull-down, RNA immunoprecipitation, and MS2 pull-down assays were used to the exploration of mechanism. A mouse model with reconstituted human immune system components (huNSG mice) was constructed to explore the role of exosomal circCCAR1 in the resistance to anti-PD1 therapy in HCC.ResultsIncreased circCCAR1 levels existed in tumor tissues and exosomes in the plasma of HCC patients, in the culture supernatant and HCC cells. CircCCAR1 accelerated the growth and metastasis of HCC in vitro and in vivo. E1A binding protein p300 (EP300) and eukaryotic translation initiation factor 4A3 (EIF4A3) promoted the biogenesis of circCCAR1, and Wilms tumor 1-associated protein (WTAP)-mediated m6A modification enhanced circCCAR1 stability by binding insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3). CircCCAR1 acted as a sponge for miR-127-5p to upregulate its target WTAP and a feedback loop comprising circCCAR1/miR-127-5p/WTAP axis was formed. CircCCAR1 is secreted by HCC cells in a heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1)-dependent manner. Exosomal circCCAR1 was taken in by CD8 + T cells and caused dysfunction of CD8 + T cells by stabilizing the PD-1 protein. CircCCAR1 promoted resistance to anti-PD1 immunotherapy. Furthermore, increased cell division cycle and apoptosis regulator 1 (CCAR1) induced by EP300 promoted the binding of CCAR1 and β-catenin protein, which further enhanced the transcription of PD-L1.ConclusionsThe circCCAR1/miR-127-5p/WTAP feedback loop enhances the growth and metastasis of HCC. Exosomal circCCAR1 released by HCC cells contributes to immunosuppression by facilitating CD8 + T-cell dysfunction in HCC. CircCCAR1 induces resistance to anti-PD1 immunotherapy, providing a potential therapeutic strategy for HCC patients.
| S-EPMC10024440 | biostudies-literature
Project description:PurposeImmune checkpoint inhibitors combined with antiangiogenic agents produce benefits in the treatment of advanced hepatocellular carcinoma (HCC). We investigated the efficacy and immunomodulatory activity of cabozantinib alone and combined with anti-PD1 in experimental models of HCC, and explored the potential target population that might benefit from this combination.Experimental designC57BL/6J mice bearing subcutaneous Hepa1-6 or Hep53.4 tumors received cabozantinib, anti-PD1, their combination, or placebo. Tumor and blood samples were analyzed by flow cytometry, IHC, transcriptome, and cytokine profiling. Cabozantinib-related effects were validated in a colorectal cancer patient-derived xenograft model. Transcriptomic data from three human HCC cohorts (cohort 1: n = 167, cohort 2: n = 57, The Cancer Genome Atlas: n = 319) were used to cluster patients according to neutrophil features, and assess their impact on survival.ResultsThe combination of cabozantinib and anti-PD1 showed increased antitumor efficacy compared with monotherapy and placebo (P < 0.05). Cabozantinib alone significantly increased neutrophil infiltration and reduced intratumor CD8+PD1+ T-cell proportions, while the combination with anti-PD1 further stimulated both effects and significantly decreased regulatory T cell (Treg) infiltration (all P < 0.05). In blood, cabozantinib and especially combination increased the proportions of overall T cells (P < 0.01) and memory/effector T cells (P < 0.05), while lowering the neutrophil-to-lymphocyte ratio (P < 0.001 for combination). Unsupervised clustering of human HCCs revealed that high tumor enrichment in neutrophil features observed with the treatment combination was linked to less aggressive tumors with more differentiated and less proliferative phenotypes.ConclusionsCabozantinib in combination with anti-PD1 enhanced antitumor immunity by bringing together innate neutrophil-driven and adaptive immune responses, a mechanism of action which favors this approach for HCC treatment.
| S-EPMC9167725 | biostudies-literature
Project description:BackgroundImmune checkpoint blockade resistance narrows the efficacy of cancer immunotherapies, but the underlying mechanism remains elusive. Delineating the inherent mechanisms of anti-PD1 resistance is important to improve outcome of patients with advanced HCC.MethodThe level of cricTMEM181 was measured in HCC patients with anti-PD1 therapy by RNA sequencing and then confirmed by qPCR and Sanger sequencing. Immune status in tumor microenvironment of HCC patients or mice models was evaluated by flow cytometry and IHC. Exosomes from HCC cell lines were isolated by ultracentrifugation, and their internalization by macrophage was confirmed by immunofluorescence. The underlying mechanism of HCC-derived exosomal circTMEM181 to macrophage was confirmed by SILAC, RNA FISH and RNA immunoprecipitation. The ATP-ADO pathway amplified by HCC-macrophage interaction was evaluated through ATP, AMP and ADO measurement and macrophage-specific CD39 knockout mice. The role of circTMEM181 in anti-PD1 therapy and its clinical significance were also determined in our retrospective HCC cohorts.ResultsHere, we found that circTMEM181 was elevated in hepatocellular carcinoma (HCC) patients responding poorly to anti-PD1 therapy and in HCC patients with a poor prognosis after operation. Moreover, we also found that high exosomal circTMEM181 favored the immunosuppressive microenvironment and endowed anti-PD1 resistance in HCC. Mechanistically, exosomal circTMEM181 sponged miR-488-3p and upregulated CD39 expression in macrophages. Using macrophage-specific CD39 knockout mice and pharmacologic approaches, we revealed a novel mode of anti-PD1 resistance in HCC. We discovered that cell-specific CD39 expression in macrophages and CD73 expression in HCC cells synergistically activated the eATP-adenosine pathway and produced more adenosine, thereby impairing CD8+ T cell function and driving anti-PD1 resistance.ConclusionIn summary, HCC-derived exosomal circTMEM181 contributes to immunosuppression and anti-PD1 resistance by elevating CD39 expression, and inhibiting the ATP-adenosine pathway by targeting CD39 on macrophages can rescue anti-PD1 therapy resistance in HCC.
| S-EPMC8627086 | biostudies-literature
Project description:BackgroundGlycogen synthase kinase 3β (GSK3β) was originally discovered to regulate glycogen synthesis and show a relationship to tumors. However, the biological functions of GSK3β in tumor-associated macrophages (TAMs) in cancers including hepatocellular carcinoma (HCC) remain unclear.MethodsThe enrichment of GSK3β in tumor tissues was assessed by Gene Expression Omnibus (GEO) database. The in vitro and in vivo assays assisted in evaluating how GSK3β in TAMs affected HCC in terms of proliferation, invasion and migration. Immunofluorescence was used to assess GSK3β expression in TAMs in the anti-PD1 therapy non-responsive HCC group and the responsive group. Western blot and coimmunoprecipitation were performed to demonstrate the interaction between GSK3β and PD-L1. We carried out in vivo experiments in a C57BL/6 mouse model of HCC established through subcutaneous injection.ResultsGEO single-cell RNA sequencing data suggested that GSK3β was highly enriched in TAMs of HCC. According to in vitro and in vivo experiments, reducing GSK3β in TAMs inhibits the cancer cell proliferation, invasion, and migration. The immunofluorescence and immunohistochemistry results confirmed that the GSK3β is significantly upregulated in TAMs of the anti-PD1 therapy non-responsive group in comparison with the responsive group. In vitro and in vivo experiments confirmed that reduced GSK3β in TAMs are capable of enhancing the sensitivity of anti-PD1 immunotherapy for HCC by decreasing PD-L1 ubiquitination. Mass spectrometry results suggested that high expression of CD14+GSK3β+ in the peripheral blood mononuclear cell (PBMC) can predict non-responsive to anti-PD1 treatment. Moreover, escitalopram is confirmed to act as GSK3β inhibitor that can increase the sensitivity of anti-PD1 immunotherapy for HCC.ConclusionsThis study revealed that macrophage GSK3β deficiency can inhibit the development of HCC by inhibiting the M2 phenotype and enhance the sensitivity of anti-PD1 immunotherapy for HCC by decreasing PD-L1 ubiquitination. The expression of CD14+GSK3β+ in PBMC can noninvasively predict anti-PD1 sensitivity in HCC patients, which provides novel strategies to predict anti-PD1 sensitivity, increase anti-PD1 therapeutic effect, and bring new hope for HCC patients.
| S-EPMC9772694 | biostudies-literature
Project description:BackgroundImmunotherapy, specifically immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 (anti-PD1), has recently received clinical approval for the treatment of adult hepatocellular carcinoma (HCC). However, the safety and efficacy of ICIs prior to solid organ transplant are unknown, especially in pediatrics. Safety reports are variable in adults, with some series describing subsequent allograft rejection and loss while others report successful transplants without allograft rejection.As ICIs stimulate the immune system by blocking the interaction between PD1 and the ligand-receptor pair programmed cell death-ligand 1 (PDL1), the downstream effects of T-cell activation increase the risk of graft rejection.MethodsHere, we present a case of an adolescent with moderately differentiated non-fibrolamellar HCC treated with pembrolizumab, an anti-PD1 therapy, who subsequently underwent successful orthotopic liver transplantation (OLT).ResultsOur patient received an OLT 138 days from the last pembrolizumab dose with graft preservation. The patient has no evidence of recurrent disease or any episode of allograft rejection 48 months post OLT. Staining of tumor and normal tissues from longitudinal specimens finds PDL1 positive Kupffer cells present in normal liver and peritumoral areas with no changes post anti-PD1 therapy. In contrast, tumor cells were negative for PDL1.ConclusionThis case represents a basis for optimism in potential use of anti-PD1 therapy in liver transplant candidates and supports further investigation of immune checkpoint inhibitors use in this unique patient population.
| S-EPMC9035049 | biostudies-literature