Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma

Chew, Valerie; Lee, Yun Hua; Pan, Lu; Nasir, Nurul Jannah Mohamed; Lim, Chun Jye; Chua, Camillus; Lai, Liyun; Hazirah, Sharifah Nur; Lim, Tony Kiat Hon; Goh, Brian K. P.; Chung, Alexander; Lo, Richard Hoau Gong; Ng, Dave Yong Xiang; Filarca, Rene L F; Albani, Salvatore; Chow, Pierce K. H.

doi:10.1136/gutjnl-2017-315485

Cited by 170 publications

(141 citation statements)

References 43 publications

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“…16 Yttrium-90 (Y90) radioembolization can augment the immune activation in patients with HCC with tumor-infiltrating lymphocytes demonstrating signs of local immune activation with higher expression of granzyme B and infiltration of CD8-positive T cells, CD56positive NK cells, and CD8-positive/CD56-positive NK T cells. 17 Peripheral blood samples before and after treatment demonstrated an increase in tumor necrosis factor (TNF)-α on both CD8-positive and CD4-positive T cells.…”

Section: Discussionmentioning

confidence: 99%

Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma

Feun

et al. 2019

Cancer

138

103

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BACKGROUND: Checkpoint inhibitors have shown modest activity in patients with advanced hepatocellular carcinoma (HCC). Herein, the authors report a prospective single-institution clinical/translational phase 2 study of pembrolizumab in patients with advanced HCC and circulating biomarkers closely related to response. METHODS: Pembrolizumab was administered at a dose of 200 mg intravenously every 3 weeks among patients who may have developed disease progression while receiving, were intolerant of, or refused sorafenib. The circulating levels of cytokines, chemokines, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and PD-L2 were correlated with response, tumor PD-L1 expression, and other clinicopathological features. RESULTS: A total of 29 patients were treated and 28 patients were evaluable for response. The most common laboratory grade 3/4 adverse events were increases in aspartate aminotransferase and/or alanine aminotransferase and serum bilirubin, which for the most part were reversible. In terms of efficacy, one patient achieved a complete response and 8 patients achieved partial responses for an overall response rate of 32%. Four other patients had stable disease. The median progression-free survival was 4.5 months and the median overall survival was 13 months. Response did not correlate with prior sorafenib therapy, PD-L1 tumor staining, or a prior history of hepatitis. Correlative studies revealed that high baseline plasma TGF-β levels (≥200 pg/mL) significantly correlated with poor treatment outcomes after pembrolizumab. Tumor PD-L1 and plasma PD-L1/PD-1 levels were associated with plasma IFN-γ or IL-10. CONCLUSIONS: Pembrolizumab was found to demonstrate activity in patients with advanced HCC. Toxicity generally was tolerable and reversible. A set of immunological markers in blood plasma as well as PD-L1 staining indicated that baseline TGF-β could be a predictive biomarker for response to pembrolizumab. Cancer 2019;125:3603-3614.

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Section: Discussionmentioning

confidence: 99%

Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma

Feun

et al. 2019

Cancer

138

103

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“…The generated files were debarcoded (CD45 + ), gated based on size and DNA content labelled with a DNA-intercalater (DVS Sciences) and live cells that were negative for cisplatin. The individual files were downsampled to 10 000-live CD45 + immune cells and analysed using in-house developed Multidimensional-Automated Reduction and Visualisation software17 based on a combination of non-linear dimensionality reduction algorithm (Barnes-Hut SNE) and k-means-clustering algorithm 20. The CyTOF data were also independently validated using FlowJo software (V.X.0.7, Tree Star) (onlinesupplementary table S1).…”

Section: Methodsmentioning

confidence: 99%

Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma

Lim

Lee

Pan

et al. 2018

Gut

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“…Cells were run on the CyAn Cyan ADP cytometer (Dako Cytomation) or on the BD LSRFortessa cell analyzer, and data were analyzed using FlowJo software (v9.8.5). Fetal thymocytes were stained as previously described and then analyzed using CyToF (Chew et al, 2019); here, we gated on fetal γδ and αβ thymocytes in order to analyze the expression of IFNγ and Tbet with FlowJo.…”

Section: Methodsmentioning

confidence: 99%

The human fetal thymus generates invariant effector γδ T cells

Tieppo

Papadopoulou

Gatti

et al. 2019

Journal of Experimental Medicine

137

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In the mouse thymus, invariant γδ T cells are generated at well-defined times during development and acquire effector functions before exiting the thymus. However, whether such thymic programming and age-dependent generation of invariant γδ T cells occur in humans is not known. Here we found that, unlike postnatal γδ thymocytes, human fetal γδ thymocytes were functionally programmed (e.g., IFNγ, granzymes) and expressed low levels of terminal deoxynucleotidyl transferase (TdT). This low level of TdT resulted in a low number of N nucleotide insertions in the complementarity-determining region-3 (CDR3) of their TCR repertoire, allowing the usage of short homology repeats within the germline-encoded VDJ segments to generate invariant/public cytomegalovirus-reactive CDR3 sequences (TRGV8-TRJP1-CATWDTTGWFKIF, TRDV2-TRDD3-CACDTGGY, and TRDV1-TRDD3-CALGELGD). Furthermore, both the generation of invariant TCRs and the intrathymic acquisition of effector functions were due to an intrinsic property of fetal hematopoietic stem and precursor cells (HSPCs) caused by high expression of the RNA-binding protein Lin28b. In conclusion, our data indicate that the human fetal thymus generates, in an HSPC/Lin28b-dependent manner, invariant γδ T cells with programmed effector functions.

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Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma

Cited by 170 publications

References 43 publications

Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma

Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma

Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma

The human fetal thymus generates invariant effector γδ T cells

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