High Expression of TGF-β1 Contributes to Hepatocellular Carcinoma Prognosis via Regulating Tumor Immunity

Jin, Xiuli; Zhang, Shuairan; Wang, Ningning; Lin, Guozhen; Shao, Chuanli; Lin, Yingbo; Liu, Jianping; Li, Yiling

doi:10.3389/fonc.2022.861601

Cited by 16 publications

(13 citation statements)

References 42 publications

(39 reference statements)

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“…Cytoplasmic ADA1 converts intracellular adenosine to inosine, and upon secretion, produces inosine in a CAR T cell membrane-proximal manner, which avoids feeding tumor cells. Third, our strategy overexpresses CD26 on the surface of CAR T cells as the CD26 expression level on the unmodified CAR T cells is relatively low and can be further downregulated by TGF-ß1, a cytokine found in significant quantities in various tumor tissues [72][73][74][75][76][77][78] . Thus, we develop a strategy to overexpress CD26 on the surface of CAR T cells, which sustains co-stimulation and membrane proximal ADA1 capture even in TGF-ß1-rich environment and provides a survival advantage for these engineered therapeutic cells.…”

Section: Discussionmentioning

confidence: 99%

Selective refueling of CAR T cells using ADA1 and CD26 boosts antitumor immunity

Hu,

Sarkar,

Song

et al. 2023

Preprint

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CAR T cell therapy has revolutionized the treatment of hematologic malignancies, but its efficacy in solid tumors remains limited due to the immunosuppressive nature of the tumor microenvironment and the inability of T cells to persist and traffic to the tumor site. While current strategies focus on enhancing CAR T cell activity through costimulatory molecules and cytokines, a critical yet often overlooked factor is the competition for nutrients between tumor cells and T cells in the nutrient-deprived tumor microenvironment. To address this challenge, we employed a selective metabolic refueling (MR) strategy by providing T cells with inosine as an alternative fuel source for growth and functionality. In this study, we engineered CAR T cells to co-express a membrane-bound CD26 and a cytoplasmic adenosine deaminase 1 (ADA1) fused to an anti-CD3 scFv. ADA1 irreversibly converts both intracellular and extracellular adenosine to inosine, overcoming adenosine-mediated immunosuppression and providing T cells with inosine for growth. The inclusion of an anti-CD3 scFv fusion partner and overexpressing CD26 boosts ADA1 capture in a membrane proximal manner, providing inosine for T cells and minimizing feeding the tumor cells. We demonstrate that ADA1 is conditionally secreted only in stress conditions and that it activates CAR T cells through trans-signaling in a tumor-specific manner. In addition, we show that, compared to unmodified CAR T cells, CD26-overexpressing CAR T cells have better migration capacity and are less susceptible to TGF-β1 suppression. Finally, we found that, in mice models of human hepatocellular carcinoma (GPC3-MR-CAR) and human non-small cell lung cancer (HER2-MR-CAR), metabolically refueled CAR T cells (MR-CAR) are more efficient in reducing tumor growth than unmodified CAR T cells. Thus, selective refueling CAR T cells using ADA1 and CD26 holds promise for improving the efficacy of CAR T cell therapy of solid tumors.

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Section: Discussionmentioning

confidence: 99%

Selective refueling of CAR T cells using ADA1 and CD26 boosts antitumor immunity

Hu,

Sarkar,

Song

et al. 2023

Preprint

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“…In addition, the Kaplan–Meier curve and ROC curve analysis were also conducted in the ICGC-LIHC-JP cohort and GSE54236 dataset to validate the robustness of the OAG score in prognosis prediction. Furthermore, we compared the predictive accuracy of the OAG signature with other risk signatures, including immune- ( 24 ), mitochondrial- ( 25 ), energy metabolism- ( 26 ), ferroptosis- ( 27 ), cuprotosis- ( 28 ), and TGF-β-related ( 29 ) signatures. The univariate and multivariate Cox regression analyses were conducted to recognize whether the OAG score was an independent prognostic factor.…”

Section: Methodsmentioning

confidence: 99%

Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma

Feng

Zhang

et al. 2023

Front. Endocrinol.

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BackgroundsThe pandemic of overweight and obesity (quantified by body mass index (BMI) ≥ 25) has rapidly raised the patient number of non-alcoholic fatty hepatocellular carcinoma (HCC), and several clinical trials have shown that BMI is associated with the prognosis of HCC. However, whether overweight/obesity is an independent prognostic factor is arguable, and the role of overweight/obesity-related metabolisms in the progression of HCC is scarcely known.Materials and methodsIn the present study, clinical information, mRNA expression profile, and genomic data were downloaded from The Cancer Genome Atlas (TCGA) as a training cohort (TCGA-HCC) for the identification of overweight/obesity-related transcriptome. Machine learning and the Cox regression analysis were conducted for the construction of the overweight/obesity-associated gene (OAG) signature. The Kaplan–Meier curve, receiver operating characteristic (ROC) curve, and the Cox regression analysis were performed to assess the prognostic value of the OAG signature, which was further validated in two independent retrospective cohorts from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). Subsequently, functional enrichment, genomic profiling, and tumor microenvironment (TME) evaluation were utilized to characterize biological activities associated with the OAG signature. GSE109211 and GSE104580 were retrieved to evaluate the underlying response of sorafenib and transcatheter arterial chemoembolization (TACE) treatment, respectively. The Genomics of Drug Sensitivity in Cancer (GDSC) database was employed for the evaluation of chemotherapeutic response.ResultsOverweight/obesity-associated transcriptome was mainly involved in metabolic processes and noticeably and markedly correlated with prognosis and TME of HCC. Afterward, a novel established OAG signature (including 17 genes, namely, GAGE2D, PDE6A, GABRR1, DCAF8L1, DPYSL4, SLC6A3, MMP3, RIBC2, KCNH2, HTRA3, PDX1, ATHL1, PRTG, SHC4, C21orf29, SMIM32, and C1orf133) divided patients into high and low OAG score groups with distinct prognosis (median overall survival (OS): 24.87 vs. 83.51 months, p < 0.0001), and the values of area under ROC curve (AUC) in predicting 1-, 2-, 3-, and 4-year OS were 0.81, 0.80, 0.83, and 0.85, respectively. Moreover, the OAG score was independent of clinical features and also exhibited a good ability for prognosis prediction in the ICGC-LIHC-JP cohort and GSE54236 dataset. Expectedly, the OAG score was also highly correlated with metabolic processes, especially oxidative-related signaling pathways. Furthermore, abundant enrichment of chemokines, receptors, MHC molecules, and other immunomodulators as well as PD-L1/PD-1 expression among patients with high OAG scores indicated that they might have better responses to immunotherapy. However, probably exclusion of T cells from infiltrating tumors resulting in lower infiltration of effective T cells would restrict immunotherapeutic effects. In addition, the OAG score was significantly associated with the response of sorafenib and TACE treatment.ConclusionsOverall, this study comprehensively disclosed the relationship between BMI-guided transcriptome and HCC. Moreover, the OAG signature had the potential clinical applications in the future to promote clinical management and precision medicine of HCC.

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“…On a molecular basis, the HCV oncogenic effect on liver parenchyma is attributed to HCV-related proteins, such as the non-structural proteins and the core protein, which modify the host genome and alter various signaling, immune, and cell-cycle pathways, while HCV via secreting pro-inflammatory cytokines, such as interferon and TGF-β promotes disease progression and hepatic carcinogenesis. Specifically, the former proteins are associated with the activation of hepatic stellate cells (HSCs), via TGF-β, which induces fibrinogenesis and enhancement of the inflammatory state [ 75 , 76 , 77 ]. Moreover, the latter protein induces the suppression of the TP53 tumor suppressor gene, as well as Retinoblastoma gene mutation significantly induces hepatic cancer cell development and growth, which is also attributed to the modified cell cycle that promotes the accumulation of several mutations.…”

Section: Hepatitis C Virus (Hcv)mentioning

confidence: 99%

Immune Microenvironment and Immunotherapeutic Management in Virus-Associated Digestive System Tumors

Sarantis

Trifylli

Koustas

et al. 2022

IJMS

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The development of cancer is a multifactorial phenomenon, while it constitutes a major global health problem. Viruses are an important factor that is involved in tumorigenesis and is associated with 12.1% of all cancer cases. Major examples of oncogenic viruses which are closely associated with the digestive system are HBV, HCV, EBV, HPV, JCV, and CMV. EBV, HPV, JCV, and CMV directly cause oncogenesis by expressing oncogenic proteins that are encoded in their genome. In contrast, HBV and HCV are correlated indirectly with carcinogenesis by causing chronic inflammation in the infected organs. In addition, the tumor microenvironment contains various immune cells, endothelial cells, and fibroblasts, as well as several growth factors, cytokines, and other tumor-secreted molecules that play a key role in tumor growth, progression, and migration, while they are closely interrelated with the virus. The presence of T-regulatory and B-regulatory cells in the tumor microenvironment plays an important role in the anti-tumor immune reaction. The tumor immune microenvironments differ in each type of cancer and depend on viral infection. The alterations in the immune microenvironment caused by viruses are also reflected in the effectiveness of immunotherapy. The present review aims at shedding light on the association between viruses and digestive system malignancies, the characteristics of the tumor immune microenvironment that develop, and the possible treatments that can be administered.

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High Expression of TGF-β1 Contributes to Hepatocellular Carcinoma Prognosis via Regulating Tumor Immunity

Cited by 16 publications

References 42 publications

Selective refueling of CAR T cells using ADA1 and CD26 boosts antitumor immunity

Selective refueling of CAR T cells using ADA1 and CD26 boosts antitumor immunity

Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma

Immune Microenvironment and Immunotherapeutic Management in Virus-Associated Digestive System Tumors

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