Functional heterogeneity of CD4+ T cells in liver inflammation

Muscate, Franziska; Woestemeier, Anna; Gagliani, Nicola

doi:10.1007/s00281-021-00881-w

Cited by 19 publications

(9 citation statements)

References 144 publications

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“…The CD8+ T cells are the main force and direct effectors to fight against tumors ( 37 , 38 ). The CD4+ T cells work as helpers to activate CD8+ T cells, enhancing antitumor performance ( 39 ). Some classical ICPs, CD274 and CTLA-4 , are immunotherapeutic targets, and the higher expression implies more curative potential ( 40 , 41 ).…”

Section: Discussionmentioning

confidence: 99%

Necroptosis throws novel insights on patient classification and treatment strategies for hepatocellular carcinoma

Gao

Shi

et al. 2022

Front. Immunol.

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IntroductionNecroptosis is a novel pattern of immunogenic cell death and has triggered an emerging wave in antitumor therapy. More evidence has suggested the potential associations between necroptosis and intra-tumoral heterogeneity. Currently, the underlying role of necroptosis remains elusive in hepatocellular carcinoma (HCC) at antitumor immunity and inter-tumoral heterogeneity.MethodsThis study enrolled a total of 728 HCC patients and 139 immunotherapy patients from eight public datasets. The consensus clustering approach was employed to depict tumor heterogeneity of cancer necroptosis. Subsequently, our study further decoded the heterogeneous clinical outcomes, genomic landscape, biological behaviors, and immune characteristics in necroptosis subtypes. For each patient, providing curative clinical recommendations and developing potential therapeutic drugs were used to promote precise medicine.ResultsWith the use of the weighted gene coexpression network analysis (WGCNA) algorithm, necroptosis-associated long non-coding RNAs (lncRNAs) (NALRs) were identified in HCC. Based on the NALR expression, two heterogeneous subtypes were decoded with distinct clinical outcomes. Compared to patients in C1, patients in C2 harbored superior pathological stage and presented more unfavorable overall survival and recurrence-free survival. Then, the robustness and reproducibility of necroptosis subtypes were further validated via the nearest template prediction (NTP) approach and classical immune phenotypes. Through comprehensive explorations, C1 was characterized by enriched immune-inflammatory and abundant immune infiltration, while C2 possessed elevated proliferative and metabolic activities and highly genomic instability. Moreover, our results indicated that C1 was more prone to obtain desirable benefits from immunotherapy. For patients in C2, numerous underlying therapeutic agents were developed, which might produce significant efficacy.ConclusionThis study identified two necroptosis subtypes with distinct characteristics, decoding the tumor heterogeneity. For an individualized patient, our work tailored corresponding treatment strategies to improve clinical management.

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Section: Discussionmentioning

confidence: 99%

Necroptosis throws novel insights on patient classification and treatment strategies for hepatocellular carcinoma

Gao

Shi

et al. 2022

Front. Immunol.

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“…This can be facilitated either by being source of proinflammatory cytokines and (auto)antibodies, but also to provide help in sustaining the inflammatory state in AIH by supporting ongoing inflammation as B cells can also act as APC in secondary in chronic immune responses [ 97 , 98 , 201 ]. Irrespective of their substantial contribution to disease maintenance and progression, T cells still seem to play the pivotal role in disease onset in AIH [ 1 – 4 , 202 ], and the use of B cell-targeted therapies as primary treatment in AIH remains questionable.…”

Section: Remarks and Current Research Gaps/outlookmentioning

confidence: 99%

B cells in autoimmune hepatitis: bystanders or central players?

2022

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B cells are central for the adaptive immune system to mount successful immune responses not only as antibody producers but also as regulators of cellular immunity. These multifaceted features are also reflected in autoimmunity where autoreactive B cells can fuel disease by production of cytotoxic autoantibodies, presentation of autoantigens to autoreactive T cells, and secretion of cytokines and chemokines that either promote detrimental immune activation or impair regulatory T and B cells. The role of B cells and autoantibodies in autoimmune hepatitis (AIH) have been controversially discussed, with typical autoantibodies and hypergammaglobulinemia indicating a key role, while strong HLA class II association suggests T cells as key players. In this review, we summarize current knowledge on B cells in AIH and how different B cell subpopulations may drive AIH progression beyond autoantibodies. We also discuss recent findings of B cell-directed therapies in AIH.

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“…CD4+ T cells recognizing the peptides presented by MHC class II molecules play an important role in protecting the liver from infections but are also involved in hepatocellular damage and autoimmunity [ 16 ]. In the liver, CD4+ T cells can acquire different cell states (i.e., T H 1, T H 2, and T H 17 cells) characterized by specific cytokine profiles, anyway during inflammation they can display a mixed phenotype showing simultaneously features of different polarization status [ 17 ].…”

Section: The Hepatic Immunological Milieumentioning

confidence: 99%

PD-1/PD-L1 Immuno-Mediated Therapy in NAFLD: Advantages and Obstacles in the Treatment of Advanced Disease

Lombardi

Piciotti

Dongiovanni

et al. 2022

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is characterized by an enhanced activation of the immune system, which predispose the evolution to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Resident macrophages and leukocytes exert a key role in the pathogenesis of NAFLD. In particular, CD4+ effector T cells are activated during the early stages of liver inflammation and are followed by the increase of natural killer T cells and of CD8+ T cytotoxic lymphocytes which contribute to auto-aggressive tissue damage. To counteract T cells activation, programmed cell death 1 (PD-1) and its ligand PDL-1 are exposed respectively on lymphocytes and liver cells’ surface and can be targeted for therapy by using specific monoclonal antibodies, such as of Nivolumab, Pembrolizumab, and Atezolizumab. Despite the combination of Atezolizumab and Bevacizumab has been approved for the treatment of advanced HCC, PD-1/PD-L1 blockage treatment has not been approved for NAFLD and adjuvant immunotherapy does not seem to improve survival of patients with early-stage HCC. In this regard, different ongoing phase III trials are testing the efficacy of anti-PD-1/PD-L1 antibodies in HCC patients as first line therapy and in combination with other treatments. However, in the context of NAFLD, immune checkpoints inhibitors may not improve HCC prognosis, even worse leading to an increase of CD8+PD-1+ T cells and effector cytokines which aggravate liver damage. Here, we will describe the main pathogenetic mechanisms which characterize the immune system involvement in NAFLD discussing advantages and obstacles of anti PD-1/PDL-1 immunotherapy.

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Functional heterogeneity of CD4+ T cells in liver inflammation

Cited by 19 publications

References 144 publications

Necroptosis throws novel insights on patient classification and treatment strategies for hepatocellular carcinoma

Necroptosis throws novel insights on patient classification and treatment strategies for hepatocellular carcinoma

B cells in autoimmune hepatitis: bystanders or central players?

PD-1/PD-L1 Immuno-Mediated Therapy in NAFLD: Advantages and Obstacles in the Treatment of Advanced Disease

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