Characteristics of Immune Response to Tumor‐Associated Antigens and Immune Cell Profile in Patients With Hepatocellular Carcinoma

Inada, Yuki; Mizukoshi, Eishiro; Seike, Takuya; Tamai, Toshikatsu; Iida, Noriho; Kitahara, Masaaki; Yamashita, Tatsuya; Arai, Kuniaki; Terashima, Toshio; Fushimi, Kazumi; Yamashita, Taro; Honda, Masao; Kaneko, Shuichi

doi:10.1002/hep.30212

Cited by 70 publications

(71 citation statements)

References 38 publications

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“…33 A second study also showed the presence of a large numbers of both effector Tregs and CTLA-4 þ CD8 þ T cells in nonalcoholic steatohepatitis-related HCC patients, whereas large numbers of PD1 þ CD8 þ T cells were observed in hepatitis B virus-related HCC patients. 34 In a third study, Treg and CD8 þ resident memory T cells were found enriched in a hepatitis B virus-related HCC microenvironment, which also was shown to contain more exhausted T cells than the microenvironment of non-viral-related HCC. 36 Despite these informative studies, a comprehensive assessment of phenotypic and functional T-cell populations in HCC still is lacking.…”

Section: Discussionmentioning

confidence: 94%

“…In recent studies the TIL landscape in HCC has been investigated using different approaches. [33][34][35][36] Single-cell transcriptome studies were performed on small numbers of cells (<150 each in 6 HCC patients) and showed the presence of different CD8 þ populations expanded from a few precursors and characterized by exhausted and regulatory T cell (Treg) signatures. 33 A second study also showed the presence of a large numbers of both effector Tregs and CTLA-4 þ CD8 þ T cells in nonalcoholic steatohepatitis-related HCC patients, whereas large numbers of PD1 þ CD8 þ T cells were observed in hepatitis B virus-related HCC patients.…”

Section: Discussionmentioning

confidence: 99%

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Unique T-Cell Populations Define Immune-Inflamed Hepatocellular Carcinoma

Blasi

Boldanova

Mori

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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Immune profiling of hepatocellular carcinoma-infiltrating cells showed unique T-cell populations, including impaired ICOS þ , TIGIT þ , CD4 þ T cells, activated CD8 þ , and non-major histocompatibility complex restricted T cells. Immunotherapy with check-point inhibitors diminished nonfunctional T cells and increased the number of responding cells.CONCLUSIONS: Unique populations of activated T cells are present in HCC tissue, whose antigen specificity remains to be investigated. Some of these cell populations are functionally impaired and nivolumab treatment restores their responsiveness. The finding of ongoing immune response within the tumor shows which lymphocyte populations are impaired within the HCC and identifies the patients who might take benefit from immunotherapy. (Cell Mol Gastroenterol Hepatol 2020;9:195-218; https://doi.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Unique T-Cell Populations Define Immune-Inflamed Hepatocellular Carcinoma

Blasi

Boldanova

Mori

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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“…This was a study to comprehensively characterize costimulatory receptor expression on CD8 + TILs and the associated T‐cell activation features in HCC patients. Previous studies describe the expression of 4‐1BB and other costimulatory receptors on CD8 + T cells, but earlier investigations have been limited in that they either used CD8 + T cells from peripheral blood or simply confirmed costimulatory receptor expression on tumor‐infiltrating T cells in HCC . In HCC, 4‐1BB expression was most prominent among the tested activation‐induced costimulatory receptors in CD8 + TILs.…”

Section: Discussionmentioning

confidence: 99%

4‐1BB Delineates Distinct Activation Status of Exhausted Tumor‐Infiltrating CD8+ T Cells in Hepatocellular Carcinoma

et al. 2019

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Background and Aims Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4‐1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor‐infiltrating CD8+ T cells (CD8+ tumor‐infiltrating lymphocytes [TILs]) and its association with distinct T‐cell activation features among exhausted CD8+ TILs in hepatocellular carcinoma (HCC). Approach and Results Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA‐sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4‐1BB was most prominently expressed on CD8+ TILs. 4‐1BB expression was almost exclusively detected on CD8+ T cells in the tumor—especially on programmed death 1 (PD‐1)high cells and not PD‐1int and PD‐1neg cells. Compared to PD‐1int and 4‐1BBnegPD‐1high CD8+ TILs, 4‐1BBposPD‐1high CD8+ TILs exhibited higher levels of tumor reactivity and T‐cell activation markers and significant enrichment for T‐cell activation gene signatures. Per‐patient analysis revealed positive correlations between percentages of 4‐1BBpos cells among CD8+ TILs and levels of parameters of tumor reactivity and T‐cell activation. Among highly exhausted PD‐1high CD8+ TILs, 4‐1BBpos cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4‐1BB–related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4‐1BB agonistic antibodies enhanced the function of CD8+ TILs and further enhanced the anti‐PD‐1–mediated reinvigoration of CD8+ TILs, especially in cases showing high levels of T‐cell activation. Conclusion 4‐1BB expression on CD8+ TILs represents a distinct activation state among highly exhausted CD8+ T cells in HCC. 4‐1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T‐cell activation.

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“…There is growing evidence that inflammation and the immune system are associated with cancer, and the tumor immune microenvironment has proven to be an important driver of biological behavior and a factor affecting chemotherapy (Pico de Coana et al, 2015;Andrejeva and Rathmell, 2017). Also, several studies have found that HCC does not adopt immune privilege, but coordinates powerful immune responses, involving innate and adaptive immune systems, which contribute to the occurrence and development of HCC (Zhou et al, 2017;Inada et al, 2019). The current research indicated the role of 18 immune-associated genes in the regulation of immune pathways and involved in tumorigenesis, which highlighted the value of 18 immuneassociated genes in the study of HCC immune mechanism.…”

Section: Discussionmentioning

confidence: 99%

Mining Prognostic Biomarkers of Hepatocellular Carcinoma Based on Immune-Associated Genes

Chen

Tang

et al. 2020

DNA and Cell Biology

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This research aims to investigate the immune-associated gene signature from databases to improve the prognostic value in hepatocellular carcinoma (HCC) by multidimensional methods using various bioinformatic methods. Fifty-one immune-associated genes were mined out, which were associated with clinical characters through univariate and multivariate Cox regression analyses, and 51 immune-associated genes could be welldivided HCC samples into high-risk and low-risk clusters. Next, we performed least absolute shrinkage and selection operator (LASSO) Cox regression method to reveal 18 immune-associated genes' signature and calculate risk score of each gene for receiver operating characteristic (ROC) analysis. Comparing with low-risk cluster, high-risk cluster had higher risk score with unfavorable prognosis. Then, multivariate Cox regression analysis showed that risk score of 18 immune-associated genes' signature was associated with tumor invasion and tumor-node-metastasis (TNM) stage. ROC analysis indicated combined TNM stage, and risk score performed more sensitive and specific than single TNM stage or risk score in survival prediction. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that the pathways enriched in tumorigenesis were related to risk score, and those pathways could separate HCC samples into high and low clusters. In addition, the survival prediction of 18 immune-associated genes' signature was well validated in independent test data set, external data set, and Real-time Quantitative PCR (RT-qPCR) experiment. The 18 immuneassociated genes' signature was constructed, which could be used in effective prediction of HCC prognosis.

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Characteristics of Immune Response to Tumor‐Associated Antigens and Immune Cell Profile in Patients With Hepatocellular Carcinoma

Cited by 70 publications

References 38 publications

Unique T-Cell Populations Define Immune-Inflamed Hepatocellular Carcinoma

Unique T-Cell Populations Define Immune-Inflamed Hepatocellular Carcinoma

4‐1BB Delineates Distinct Activation Status of Exhausted Tumor‐Infiltrating CD8+ T Cells in Hepatocellular Carcinoma

Mining Prognostic Biomarkers of Hepatocellular Carcinoma Based on Immune-Associated Genes

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