Association Between Expression Level of PD1 by Tumor-Infiltrating CD8+ T Cells and Features of Hepatocellular Carcinoma

Kim, Hyung‐Don; Song, Gi‐Won; Park, Seongyeol; Jung, M.; Kim, Min Hwan; Kang, Hyo Jeong; Yoo, Changhoon; Yi, Kijong; Kim, Kyung Hwan; Eo, Sukyeong; Moon, Deok‐Bog; Hong, Seung‐Mo; Ju, Young Seok; Shin, Eui‐Cheol; Hwang, Shin; Park, Su–Hyung

doi:10.1053/j.gastro.2018.08.030

Cited by 223 publications

(246 citation statements)

References 43 publications

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“…Another interesting finding is that 4‐1BB was almost exclusively expressed on PD‐1 high CD8 + TILs, which reportedly represent highly exhausted and tumor‐reactive CD8 + TILs . We recently demonstrated that PD‐1 high CD8 + TILs exhibit features of more progressed T‐cell exhaustion compared to PD‐1 int and PD‐1 neg CD8 + TILs and that HCCs with higher proportions of PD‐1 high CD8 + TILs are enriched for the T‐cell–inflamed gene signature .…”

Section: Discussionmentioning

confidence: 92%

“…We recently demonstrated that PD‐1 + CD8 + TILs from HCC patients can be subdivided into PD‐1 int and PD‐1 high CD8 + TILs and that the latter group shows features of more‐severe T‐cell exhaustion . Another recent study found that PD‐1 high CD8 + TILs exhibit high tumor reactivity .…”

Section: Resultsmentioning

confidence: 99%

“…Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood by standard Ficoll‐Paque (GE Healthcare, Uppsala, Sweden) density gradient centrifugation. Intrahepatic lymphocytes (IHLs) and TILs were isolated from tissue samples as described . Briefly, tissue samples were cut into small pieces (2‐4 mm) and then transferred to a gentle MACS C‐Tube containing a mixture of enzymes (Milteny Biotec, Bergisch Gladbach, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Intrahepatic lymphocytes (IHLs) and TILs were isolated from tissue samples as described. (18) Briefly, tissue samples were cut into small pieces (2-4 mm) and then transferred to a gentle MACS C-Tube containing a mixture of enzymes (Milteny Biotec, Bergisch Gladbach, Germany). Next, samples were mechanically homogenized and enzymatically digested using the gentle MACS Octo Dissociator (Milteny Biotec).…”

Section: Study Patients and Clinical Samplesmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Study Patients and Clinical Samplesmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2019

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“…Data are still lacking regarding clinical efficacy of inhibiting checkpoint molecules, other than CTLA4 and PD1 expressed in T cells infiltrating HCC. Co‐expression of multiple inhibitory receptors indicates T cell exhaustion as reported in T cells infiltrating melanoma and HCC . The degree of functional impairment of T cells infiltrating HCC has been related to the number of checkpoint molecules expressed, with combined checkpoint blockade showing synergistic effect and increased functional rescue .…”

Section: Introductionmentioning

confidence: 99%

Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications

Cariani

Missale

2019

Liver International

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The development of immunotherapy for solid tumours has boosted interest in the contexture of tumour immune microenvironment (TIME). Several lines of evidence indicate that the interplay between tumour cells and TIME components is a key factor for the evolution of hepatocellular carcinoma (HCC) and for the likelihood of response to immunotherapeutics. The availability of high‐resolution methods will be instrumental for a better definition of the complexity and diversity of TIME with the aim of predicting disease outcome, treatment response and possibly new therapeutic targets. Here, we review current knowledge about the immunological mechanisms involved in shaping the clinical course of HCC. Effector cells, regulatory cells and soluble mediators are discussed for their role defining TIME and as targets for immune modulation, together with possible immune signatures for optimization of immunotherapeutic strategies.

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Molecular subtyping of hepatocellular carcinoma: A step toward precision medicine

Liu

2020

Cancer Communications

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Hepatocellular carcinoma (HCC) is one of the most prevalent and fatal digestive tumors. Treatment for this disease has been constraint by heterogeneity of this group of tumors, which has greatly limited the progress in personalized therapy. Although existing studies have revealed the genetic and epigenetic blueprints that drive HCCs, many of the molecular mechanisms that lead to HCCs remain elusive. Recent advances in techniques for studying functional genomics, such as genome sequencing and transcriptomic analyses, have led to the discovery of molecular mechanisms that participate in the initiation and evolution of HCC. Integrative multi‐omics analyses have identified several molecular subtypes of HCC associated with specific molecular characteristics and clinical outcomes. Deciphering similar molecular features among highly heterogeneous HCC patients is a prerequisite to implementation of personalized therapeutics. This review summarizes the current research progresses in precision therapy on the backbone of molecular subtypes of HCC.

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Association Between Expression Level of PD1 by Tumor-Infiltrating CD8+ T Cells and Features of Hepatocellular Carcinoma

Cited by 223 publications

References 43 publications

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

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

Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications

Molecular subtyping of hepatocellular carcinoma: A step toward precision medicine

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