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T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (1 June 2021) | Viewed by 42147

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Special Issue Editors

Dr. Paola Fisicaro

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Guest Editor

Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero, Universitaria di Parma, Parma, Italy
Interests: T cells

Dr. Carolina Boni

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Guest Editor

Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
Interests: viral hepatitis immunopathogenesis; chronic HBV infection; T cell exhaustion; immunological correlates of protection; immune therapeutic strategies

Special Issue Information

Dear Colleagues,

In chronic viral hepatitis and in hepatocarcinoma (HCC), antigen-specific T cells are described as functionally defective. T cell impairment is characterized by a progressive and hierarchical loss of T cell functions, depending on the duration of T cell exposure to high antigen loads.

Various evidence of dysfunction have also been observed for NK cells, which can play a pathogenetic role, exerting a regulatory activity on adaptive immune responses in both the setting of chronic viral hepatitis and HCC.

Further inhibitory mechanisms contributing to T and NK cell dysfunction are represented by the up-regulation of inhibitory receptors; transcriptional, metabolic, and epigenetic deregulation; nutrient depletion in the hepatic microenvironment; expansion of negative regulatory T and myeloid-derived suppressor cells (gMDSC); and the effect of suppressive cytokines.

Based on these lines of evidence, immune modulatory therapies are widely believed to represent potential therapeutic strategies for chronic viral hepatitis and HCC, and new immunotherapeutic approaches are being tested for clinical translation.

This Special Issue will highlight the present knowledge about the emerging cell-based immune-therapeutic strategies, aimed at reconstituting an efficient T/NK cell response in chronic viral hepatitis and in hepatocarcinoma, including immune checkpoint blockers, metabolic cell modulation, therapeutic vaccines, and T and NK cell engineering.

Dr. Paola Fisicaro
Dr. Carolina Boni
Guest Editors

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Keywords

chronic viral hepatitis
chronic HBV infection
hepatocarcinoma
T cell exhaustion
NK cells
immune-therapy
immunoregulatory mechanisms
CAR T cells
therapeutic vaccination
checkpoint blockade

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Published Papers (10 papers)

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Editorial

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3 pages, 189 KiB

Open AccessEditorial

T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma

by Paola Fisicaro and Carolina Boni

Cells 2022, 11(2), 180; https://doi.org/10.3390/cells11020180 - 6 Jan 2022

Cited by 4 | Viewed by 2084

Abstract

In chronic viral hepatitis and in hepatocarcinoma (HCC), antigen-specific T cells are deeply exhausted, and evidence of dysfunction has also been observed for NK cells, which can play a pathogenetic role, exerting a regulatory activity on adaptive immune responses [...] Full article

(This article belongs to the Special Issue T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma)

Research

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15 pages, 2112 KiB

Open AccessArticle

Phenotypic Characterization by Single-Cell Mass Cytometry of Human Intrahepatic and Peripheral NK Cells in Patients with Hepatocellular Carcinoma

by Yuichi Yoshida, Sachiyo Yoshio, Taiji Yamazoe, Taizo Mori, Yuriko Tsustui, Hironari Kawai, Shiori Yoshikawa, Takasuke Fukuhara, Toru Okamoto, Yoshihiro Ono, Yu Takahashi, Ryuki Hashida, Takumi Kawaguchi, Akinobu Taketomi and Tatsuya Kanto

Cells 2021, 10(6), 1495; https://doi.org/10.3390/cells10061495 - 14 Jun 2021

Cited by 10 | Viewed by 4162

Abstract

Overall response rates of systemic therapies against advanced hepatocellular carcinoma (HCC) remain unsatisfactory. Thus, searching for new immunotherapy targets is indispensable. NK cells are crucial effectors and regulators in the tumor microenvironment and a determinant of responsiveness to checkpoint inhibitors. We revealed the landscape of NK cell phenotypes in HCC patients to find potential immunotherapy targets. Using single cell mass cytometry, we analyzed 32 surface markers on CD56^dim and CD56^bright NK cells, which included Sialic acid-binding immunoglobulin-type lectins (Siglecs). We compared peripheral NK cells between HCC patients and healthy volunteers. We also compared NK cells, in terms of their localizations, on an individual patient bases between peripheral and intrahepatic NK cells from cancerous and noncancerous liver tissues. In the HCC patient periphery, CD160⁺CD56^dim NK cells that expressed Siglec-7, NKp46, and NKp30 were reduced, while CD49a⁺CD56^dim NK cells that expressed Siglec-10 were increased. CD160 and CD49a on CD56^dim NK cells were significantly correlated to other NK-related markers in HCC patients, which suggested that CD160 and CD49a were signature molecules. CD49a⁺ CX3CR1⁺ Siglec-10⁺ NK cells had accumulated in HCC tissues. Considering further functional analyses, CD160, CD49a, CX3CR1, and Siglec-10 on CD56^dim NK cells may be targets for immunotherapies of HCC patients. Full article

(This article belongs to the Special Issue T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma)

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16 pages, 2301 KiB

Open AccessArticle

Adaptive Subsets Limit the Anti-Tumoral NK-Cell Activity in Hepatocellular Carcinoma

by Charlotte Rennert, Catrin Tauber, Pia Fehrenbach, Kathrin Heim, Dominik Bettinger, Özlem Sogukpinar, Anita Schuch, Britta Franziska Zecher, Bertram Bengsch, Sven A. Lang, Peter Bronsert, Niklas K. Björkström, Stefan Fichtner-Feigl, Michael Schultheiss, Robert Thimme and Maike Hofmann

Cells 2021, 10(6), 1369; https://doi.org/10.3390/cells10061369 - 2 Jun 2021

Cited by 9 | Viewed by 3831

Abstract

Hepatocellular carcinoma (HCC) is a global health burden with increasing incidence, poor prognosis and limited therapeutic options. Natural killer (NK) cells exhibit potent anti-tumoral activity and therefore represent potential targets for immunotherapeutic approaches in HCC treatment. However, the anti-tumoral activity of NK cells in HCC associated with different etiologies, and the impact of the heterogeneous NK cell subset, e.g., adaptive and conventional subsets, are not understood in detail. By comparatively analyzing the NK-cell repertoire in 60 HCC patients, 33 liver cirrhosis patients and 36 healthy donors (HD), we show in this study that the NK-cell repertoire is linked to HCC etiology, with increased frequencies of adaptive NK cells in Hepatitis B virus (HBV)-associated HCC. Adaptive NK cells exhibited limited anti-tumoral activity toward liver cancer cells; however, this was not a result of a specific NK-cell impairment in HCC but rather represented an intrinsic feature, since the characteristics of circulating and intra-tumoral adaptive NK cells were conserved between HD, HCC and liver cirrhosis patients. Hence, the expansion of adaptive NK cells with reduced anti-tumoral activity, detectable in HBV-associated HCC, may have implications for tumor surveillance and therapy. Full article

(This article belongs to the Special Issue T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma)

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18 pages, 6139 KiB

Open AccessArticle

Intratumor Regulatory Noncytotoxic NK Cells in Patients with Hepatocellular Carcinoma

by Alessandra Zecca, Valeria Barili, Danila Rizzo, Andrea Olivani, Elisabetta Biasini, Diletta Laccabue, Raffaele Dalla Valle, Carlo Ferrari, Elisabetta Cariani and Gabriele Missale

Cells 2021, 10(3), 614; https://doi.org/10.3390/cells10030614 - 10 Mar 2021

Cited by 27 | Viewed by 4301

Abstract

Previous studies support the role of natural killer (NK) cells in controlling hepatocellular carcinoma (HCC) progression. However, ambiguity remains about the multiplicity and the role of different NK cell subsets, as a pro-oncogenic function has been suggested. We performed phenotypic and functional characterization of NK cells infiltrating HCC, with the corresponding nontumorous tissue and liver from patients undergoing liver resection for colorectal liver metastasis used as controls. We identified a reduced number of NK cells in tumors with higher frequency of CD56^BRIGHTCD16⁻ NK cells associated with higher expression of NKG2A, NKp44, and NKp30 and downregulation of NKG2D. Liver-resident (CXCR6⁺) NK cells were reduced in the tumors where T-bet^hiEomes^lo expression was predominant. HCCs showed higher expression of CD49a with particular enrichment in CD49a⁺Eomes⁺ NK cells, a subset typically represented in the decidua and playing a proangiogenic function. Functional analysis showed reduced TNF-α production along with impaired cytotoxic capacity that was inversely related to CXCR6⁻, T-bet^hiEomes^lo, and CD49a⁺Eomes⁺ NK cells. In conclusion, we identified a subset of NK cells infiltrating HCC, including non-liver-resident cells that coexpressed CD49a and Eomes and showed reduced cytotoxic potential. This NK cell subset likely plays a regulatory role in proangiogenic function. Full article

(This article belongs to the Special Issue T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma)

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Review

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22 pages, 1504 KiB

Open AccessReview

Unraveling the Multifaceted Nature of CD8 T Cell Exhaustion Provides the Molecular Basis for Therapeutic T Cell Reconstitution in Chronic Hepatitis B and C

by Valeria Barili, Andrea Vecchi, Marzia Rossi, Ilaria Montali, Camilla Tiezzi, Amalia Penna, Diletta Laccabue, Gabriele Missale, Paola Fisicaro and Carolina Boni

Cells 2021, 10(10), 2563; https://doi.org/10.3390/cells10102563 - 28 Sep 2021

Cited by 12 | Viewed by 4420

Abstract

In chronic hepatitis B and C virus infections persistently elevated antigen levels drive CD8+ T cells toward a peculiar differentiation state known as T cell exhaustion, which poses crucial constraints to antiviral immunity. Available evidence indicates that T cell exhaustion is associated with a series of metabolic and signaling deregulations and with a very peculiar epigenetic status which all together lead to reduced effector functions. A clear mechanistic network explaining how intracellular metabolic derangements, transcriptional and signaling alterations so far described are interconnected in a comprehensive and unified view of the T cell exhaustion differentiation profile is still lacking. Addressing this issue is of key importance for the development of innovative strategies to boost host immunity in order to achieve viral clearance. This review will discuss the current knowledge in HBV and HCV infections, addressing how innate immunity, metabolic derangements, extensive stress responses and altered epigenetic programs may be targeted to restore functionality and responsiveness of virus-specific CD8 T cells in the context of chronic virus infections. Full article

(This article belongs to the Special Issue T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma)

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23 pages, 2557 KiB

Open AccessReview

Prospects and Challenges for T Cell-Based Therapies of HCC

by Norman Woller, Sophie Anna Engelskircher, Thomas Wirth and Heiner Wedemeyer

Cells 2021, 10(7), 1651; https://doi.org/10.3390/cells10071651 - 30 Jun 2021

Cited by 18 | Viewed by 4384

Abstract

The scope of therapeutic options for the treatment of hepatocellular carcinoma (HCC) has recently been expanded by immunotherapeutic regimens. T cell-based therapies, especially in combination with other treatments have achieved far better outcomes compared to conventional treatments alone. However, there is an emerging body of evidence that eliciting T cell responses in immunotherapeutic approaches is insufficient for favorable outcomes. Immune responses in HCC are frequently attenuated in the tumor microenvironment (TME) or may even support tumor progress. Hence, therapies with immune checkpoint inhibitors or adoptive cell therapies appear to necessitate additional modification of the TME to unlock their full potential. In this review, we focus on immunotherapeutic strategies, underlying molecular mechanisms of CD8 T cell immunity, and causes of treatment failure in HCC of viral and non-viral origin. Furthermore, we provide an overview of TME features in underlying etiologies of HCC patients that mediate therapy resistance to checkpoint inhibition and discuss strategies from the literature concerning current approaches to these challenges. Full article

(This article belongs to the Special Issue T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma)

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18 pages, 830 KiB

Open AccessFeature PaperReview

Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches

by Suresh Gopi Kalathil and Yasmin Thanavala

Cells 2021, 10(6), 1332; https://doi.org/10.3390/cells10061332 - 28 May 2021

Cited by 36 | Viewed by 7323

Abstract

Natural killer (NK) cells account for 25–50% of the total number of hepatic lymphocytes, which implicates that NK cells play an important role in liver immunity. The frequencies of both circulating and tumor infiltrating NK cells are positively correlated with survival benefit in hepatocellular cancer (HCC) and have prognostic implications, which suggests that functional impairment in NK cells and HCC progression are strongly associated. In HCC, T cell exhaustion is accompanied by the interaction between immune checkpoint ligands and their receptors on tumor cells and antigen presenting cells (APC). Immune checkpoint inhibitors (ICIs) have been shown to interfere with this interaction and have altered the therapeutic landscape of multiple cancer types including HCC. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as first-line therapy for HCC. NK cells are the first line effectors in viral hepatitis and play an important role by directly eliminating virus infected cells or by activating antigen specific T cells through IFN-γ production. Furthermore, chimeric antigen receptor (CAR)-engineered NK cells and T cells offer unique opportunities to create CAR-NK with multiple specificities learning from the experience gained with CAR-T cells with potentially less adverse effects. This review focus on the abnormalities of NK cells, T cells, and their functional impairment in patients with chronic viral hepatitis, which contributes to progression to hepatic malignancy. Furthermore, we discuss and summarize recent advances in the NK cell and T cell based immunotherapeutic approaches in HCC. Full article

(This article belongs to the Special Issue T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma)

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14 pages, 2017 KiB

Open AccessReview

CD4⁺ T Cells in Chronic Hepatitis B and T Cell-Directed Immunotherapy

by Sonja I. Buschow and Diahann T. S. L. Jansen

Cells 2021, 10(5), 1114; https://doi.org/10.3390/cells10051114 - 6 May 2021

Cited by 28 | Viewed by 4211

Abstract

The impaired T cell responses observed in chronic hepatitis B (HBV) patients are considered to contribute to the chronicity of the infection. Research on this impairment has been focused on CD8⁺ T cells because of their cytotoxic effector function; however, CD4⁺ T cells are crucial in the proper development of these long-lasting effector CD8⁺ T cells. In this review, we summarize what is known about CD4⁺ T cells in chronic HBV infection and discuss the importance and opportunities of including CD4⁺ T cells in T cell-directed immunotherapeutic strategies to cure chronic HBV. Full article

(This article belongs to the Special Issue T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma)

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16 pages, 8348 KiB

Open AccessReview

Gamma-Chain Receptor Cytokines & PD-1 Manipulation to Restore HCV-Specific CD8⁺ T Cell Response during Chronic Hepatitis C

by Julia Peña-Asensio, Henar Calvo, Miguel Torralba, Joaquín Miquel, Eduardo Sanz-de-Villalobos and Juan-Ramón Larrubia

Cells 2021, 10(3), 538; https://doi.org/10.3390/cells10030538 - 3 Mar 2021

Cited by 6 | Viewed by 3214

Abstract

Hepatitis C virus (HCV)-specific CD8⁺ T cell response is essential in natural HCV infection control, but it becomes exhausted during persistent infection. Nowadays, chronic HCV infection can be resolved by direct acting anti-viral treatment, but there are still some non-responders that could benefit from CD8⁺ T cell response restoration. To become fully reactive, T cell needs the complete release of T cell receptor (TCR) signalling but, during exhaustion this is blocked by the PD-1 effect on CD28 triggering. The T cell pool sensitive to PD-1 modulation is the progenitor subset but not the terminally differentiated effector population. Nevertheless, the blockade of PD-1/PD-L1 checkpoint cannot be always enough to restore this pool. This is due to the HCV ability to impair other co-stimulatory mechanisms and metabolic pathways and to induce a pro-apoptotic state besides the TCR signalling impairment. In this sense, gamma-chain receptor cytokines involved in memory generation and maintenance, such as low-level IL-2, IL-7, IL-15, and IL-21, might carry out a positive effect on metabolic reprogramming, apoptosis blockade and restoration of co-stimulatory signalling. This review sheds light on the role of combinatory immunotherapeutic strategies to restore a reactive anti-HCV T cell response based on the mixture of PD-1 blocking plus IL-2/IL-7/IL-15/IL-21 treatment. Full article

(This article belongs to the Special Issue T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma)

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Other

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4 pages, 638 KiB

Open AccessCommentary

Personalized Armored TCR-Redirected T Cell Therapy for Liver/Organ Transplant with Recurrent Cancer

by Morteza Hafezi, Anthony Tan and Antonio Bertoletti

Cells 2021, 10(8), 1861; https://doi.org/10.3390/cells10081861 - 22 Jul 2021

Cited by 4 | Viewed by 3015

Abstract

Hepatitis B virus-related hepatocellular carcinoma recurrence after liver transplantation (LT) is notoriously difficult to manage and fatal. As a therapeutic option, adoptive cell therapy with HBV-specific TCR-redirected T cells could be employed to target and control relapses in these patients. However, indispensable immunosuppressive medications post-transplantation can significantly hinder the optimum efficacy of such therapy in the clinic. Here we report a new class of Armored TCR T cells which are able to attack recurrent cancer cells in liver transplanted recipients, while temporarily evading immunosuppressant drugs. We believe this strategy could open up new opportunities for treating pathologies under immunosuppressant treatment. Full article

(This article belongs to the Special Issue T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma)

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