Modelling immune cytotoxicity for cholangiocarcinoma with tumour-derived organoids and effector T cells.

Background: Immunotherapy with immune checkpoint inhibitors (ICIs) is being explored to improve cholangiocarcinoma (CCA) therapy. However, it remains difficult to predict which ICI will be effective for individual patients. Therefore, the aim of this study is to develop a co-culture method with patient-derived CCA organoids and immune cells, which could represent anti-cancer immunity in vitro.

An Engineered IL15 Cytokine Mutein Fused to an Anti-PD1 Improves Intratumoral T-cell Function and Antitumor Immunity.

The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. Here, we set out to address these challenges by engineering a fusion protein of a single, potency-reduced, IL15 mutein and a PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed to deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation to PD1 tumor-infiltrating lymphocytes (TIL) while minimally affecting circulating peripheral natural killer (NK) cells and T cells.

TIGIT, the Next Step Towards Successful Combination Immune Checkpoint Therapy in Cancer.

T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory receptor expressed on several types of lymphocytes. Efficacy of antibody blockade of TIGIT in cancer immunotherapy is currently widely being investigated in both pre-clinical and clinical studies. In multiple cancers TIGIT is expressed on tumor-infiltrating cytotoxic T cells, helper T cells, regulatory T cells and NK cells, and its main ligand CD155 is expressed on tumor-infiltrating myeloid cells and upregulated on cancer cells, which contributes to local suppression of immune-surveillance.

Expression of Cancer Testis Antigens in Tumor-Adjacent Normal Liver Is Associated with Post-Resection Recurrence of Hepatocellular Carcinoma.

High recurrence rates after resection of hepatocellular carcinoma (HCC) with curative intent impair clinical outcomes of HCC. Cancer/testis antigens (CTAs) are suitable targets for cancer immunotherapy if selectively expressed in tumor cells. The aims were to identify CTAs that are frequently and selectively expressed in HCC-tumors, and to investigate whether CTAs could serve as biomarkers for occult metastasis.

Detection of oncogenic mutations in paired circulating tumor DNA and circulating tumor cells in patients with hepatocellular carcinoma.

Background And Aims: Circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) may be used for diagnostic or prognostic purposes in patients with hepatocellular carcinoma (HCC). We aim to determine whether CTCs or ctDNA are suitable to determine oncogenic mutations in HCC patients.

Methods: Twenty-six mostly advanced HCC patients were enrolled.

TIGIT and PD1 Co-blockade Restores ex vivo Functions of Human Tumor-Infiltrating CD8 T Cells in Hepatocellular Carcinoma.

Background & Aims: TIGIT is a co-inhibitory receptor, and its suitability as a target for cancer immunotherapy in HCC is unknown. PD1 blockade is clinically effective in about 20% of advanced HCC patients. Here we aim to determine whether co-blockade of TIGIT/PD1 has added value to restore functionality of HCC tumor-infiltrating T cells (TILs).

Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance.

Background & Aims: Cancer-associated fibroblasts (CAFs) play a key role in the cancer process, but the research progress is hampered by the paucity of preclinical models that are essential for mechanistic dissection of cancer cell-CAF interactions. Here, we aimed to establish 3-dimensional (3D) organotypic co-cultures of primary liver tumor-derived organoids with CAFs, and to understand their interactions and the response to treatment.

Methods: Liver tumor organoids and CAFs were cultured from murine and human primary liver tumors.

Long noncoding RNA SchLAH suppresses metastasis of hepatocellular carcinoma through interacting with fused in sarcoma.

Emerging evidence has indicated that deregulation of long non-coding RNAs (lncRNAs) can contribute to the progression and metastasis of human cancer, including hepatocellular carcinoma (HCC). However, the roles of most lncRNAs in HCC remain largely unknown. Here we found a long noncoding RNA termed SchLAH (seven chromosome locus associated with HCC; also called BC035072) was generally downregulated in HCC.

Loss of FBP1 facilitates aggressive features of hepatocellular carcinoma cells through the Warburg effect.

Reprogrammed metabolism has been identified as an emerging hallmark in cancer cells. It has been demonstrated that fructose-1, 6-bisphosphatase 1 (FBP1) as a rate-limiting enzyme in gluconeogenesis plays critical roles in tumor initiation and progression in several cancer types. However, function of FBP1 in hepatocellular carcinoma (HCC) is still not clear.

Hsa_circ_0001649: A circular RNA and potential novel biomarker for hepatocellular carcinoma.

Background: It has been shown that circular RNA (circRNA) is associated with human cancers, however, few studies have been reported in hepatocellular carcinoma (HCC).

Objective: To estimate clinical values of a circular RNA, Hsa_circ_0001649, in HCC.

Methods: Expression level of hsa_circ_0001649 was detected in HCC and paired adjacent liver tissues by real-time quantitative reverse transcription-polymerase chain reactions (qRT-PCRs).

KDM6B Elicits Cell Apoptosis by Promoting Nuclear Translocation of FOXO1 in Non-Small Cell Lung Cancer.

Background/aims: Non-small cell lung carcinoma (NSCLC) is the most common type of lung cancer and the cause of most cancer-related deaths. The molecular mechanisms that are involved in NSCLC development are currently not well understood. Accumulating evidence shows that histone demethylases play important roles in the regulation of pathological developmental processes in many diseases, including various types of cancers.

Diagnostic values of alpha-fetoprotein, dickkopf-1, and osteopontin for hepatocellular carcinoma.

The timely diagnosis and effective treatment are essential for improving the survival and prognosis of hepatocellular carcinoma (HCC) patients. Alpha-fetoprotein (AFP) is the most widely used biomarker for diagnosis of HCC, but the low sensitivity and specificity limits its clinical application. In this study, we evaluated the diagnostic capability of the combination of AFP with two novel potential biomarkers, dickkopf-1 (DKK1) and osteopontin (OPN), for HCC in 390 participants including 89 patients with HCC, 36 patients with liver cirrhosis, 65 patients with chronic hepatitis B, and 200 health controls.

Hepatic stellate cells activated by acidic tumor microenvironment promote the metastasis of hepatocellular carcinoma via osteopontin.

Extracellular pH of solid tumor is generally acidic due to excessive glycolysis and poor perfusion. But whether acidic tumor microenvironment influenced the stromal cells infiltrating in tumor remains unknown. As the predominant progenitor of stromal cells in liver, the number of activated hepatic stellate cells (HSCs) was found positively correlated to the acidification level in the tumor tissues of HCC patients in our study.