Activation and transcriptional profile of monocytes and CD8+ T cells are altered in checkpoint inhibitor-related hepatitis

Gudd, Cathrin; Au, Lewis; Triantafyllou, Evangelos; Shum, Benjamin; Liu, Tong; Nathwani, Rooshi; Kumar, Naveenta; Mukherjee, Sujit; Dhar, Ameet; Woollard, Kevin J.; Yone, You; Pinato, David J.; Thursz, Mark; Goldin, Robert; Gore, Martin; Larkin, James; Khamri, Wafa; Antoniades, Charalambos; Turajlic, Samra; Possamai, Lucia

doi:10.1016/j.jhep.2021.02.008

Cited by 41 publications

(71 citation statements)

References 49 publications

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“…A recent analysis of phenotypic and transcriptional profiling of peripheral immune subsets of patients treated with ICIs and developing hepatitis showed the presence of activated monocytes and enhanced effector CD8 + T cells, compared to those without hepatitis and healthy controls. To support this, CD163 + /CCR2 + macrophages and CD8 + T cells were found in liver inflammation infiltrate ( Gudd et al, 2021 ).…”

Section: Proposed Immunopathogenic Mechanisms For Iraesmentioning

confidence: 93%

Biological Bases of Immune-Related Adverse Events and Potential Crosslinks With Immunogenic Effects of Radiation

Bardoscia¹,

Pasinetti

Triggiani

et al. 2021

Front. Pharmacol.

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Immune checkpoint inhibitors have gained an established role in the treatment of different tumors. Indeed, their use has dramatically changed the landscape of cancer care, especially for tumor types traditionally known to have poor outcomes. However, stimulating anticancer immune responses may also elicit an unusual pattern of immune-related adverse events (irAEs), different from those of conventional chemotherapy, likely due to a self-tolerance impairment featuring the production of autoreactive lymphocytes and autoantibodies, or a non-specific autoinflammatory reaction. Ionizing radiation has proven to promote both positive pro-inflammatory and immunostimolatory activities, and negative anti-inflammatory and immunosuppressive mechanisms, as a result of cross-linked interactions among radiation dose, the tumor microenvironment and the host genetic predisposition. Several publications argue in favor of combining immunotherapy and a broad range of radiation schedules, based on the recent evidence of superior treatment responses and patient survival. The synergistic modulation of the immune response by radiation therapy and immunotherapeutics, particularly those manipulating T-cell activation, may also affect the type and severity of irAEs, suggesting a relationship between the positive antitumor and adverse autoimmune effects of these agents. As yet, information on factors that may help to predict immune toxicity is still lacking. The aim of our work is to provide an overview of the biological mechanisms underlying irAEs and possible crosslinks with radiation-induced anticancer immune responses. We believe such an overview may support the optimization of immunotherapy and radiotherapy as essential components of multimodal anticancer therapeutic approaches. Challenges in translating these to clinical practice are discussed.

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Section: Proposed Immunopathogenic Mechanisms For Iraesmentioning

confidence: 93%

Biological Bases of Immune-Related Adverse Events and Potential Crosslinks With Immunogenic Effects of Radiation

Bardoscia¹,

Pasinetti

Triggiani

et al. 2021

Front. Pharmacol.

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“…Anti-CTLA-4 therapy has been shown to induce the expansion of Th1 cells thereby increasing the levels of proinflammatory cytokines (IL-2, IFN- γ , TNF) production, which can go on to activate CTLs, as well as innate immune cells such as macrophages and natural killer cells 62 . This indirect effect on innate immune cells via altering Th-mediated cytokine production may be particularly important in ILICI and hepatotoxicity where monocytes have been implicated in the pathogenesis of injury 96 . Another example of immune-related toxicity from the indirect effect of ICIs on innate immunity was the observed correlation of neutrophil activation markers such as CD177 and carcinoembryonic antigen-related cell adhesion molecule (CEACAM1) in the sera of a subset of patients who went on to develop ipilimumab-induced colitis and GI toxicity 97 .…”

Section: Immune-mediated Liver Injury Caused By Checkpoint Inhibitors (Ilici)mentioning

confidence: 99%

“…Expansion of Th1 cells and increase in pro-inflammatory cytokines leading to activation of CTLs, monocytes and macrophages 62 , 95 , 96 …”

Section: Immune-mediated Liver Injury Caused By Checkpoint Inhibitors (Ilici)mentioning

confidence: 99%

Mechanisms of immune checkpoint inhibitor-mediated liver injury

Shojaie

Ali

Iorga

et al. 2021

Acta Pharmaceutica Sinica B

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The immune checkpoints, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein-1/ligand-1 (PD-1/PD-L1) are vital contributors to immune regulation and tolerance. Recently immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, they come with the cost of immune related adverse events involving multiple organs such as the liver. Due to its constant exposure to foreign antigens, the liver has evolved a high capacity for immune tolerance, therefore, blockade of the immune checkpoints can result in aberrant immune activation affecting the liver in up to 20% of patients depending on the agent(s) used and underlying factors. This type of hepatotoxicity is termed immune mediated liver injury from checkpoint inhibitors (ILICI) and is more common when CTLA4 and PD-1/PD-L1 are used in combination. The underlying mechanisms of this unique type of hepatotoxicity are not fully understood; however, the contribution of CD8 + cytotoxic T lymphocytes, various CD4 + T cells populations, cytokines, and the secondary activation of the innate immune system leading to liver injury have all been suggested. This review summarizes our current understanding of the underlying mechanisms of liver injury in immunotherapy using animal models of ILICI and available patient data from clinical studies.

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“…Recent evidence shows activation of the peripheral monocyte cellular compartment together with increased activity of cytotoxic CD8+ T lymphocytes. These peripheral phenomena are reflected by liver inflammation dominated by co-localised CD8+ lymphocytes and CCR2+ macrophages [ 107 ]. Further research is needed to validate these preliminary, descriptive findings as biomarkers and to further understand the pathogenesis of ICI-induced hepatitis.…”

Section: Immunology Of Dilimentioning

confidence: 99%

Immune-Mediated Drug-Induced Liver Injury: Immunogenetics and Experimental Models

Gerussi

Natalini

Antonangeli

et al. 2021

IJMS

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Drug-induced liver injury (DILI) is a challenging clinical event in medicine, particularly because of its ability to present with a variety of phenotypes including that of autoimmune hepatitis or other immune mediated liver injuries. Limited diagnostic and therapeutic tools are available, mostly because its pathogenesis has remained poorly understood for decades. The recent scientific and technological advancements in genomics and immunology are paving the way for a better understanding of the molecular aspects of DILI. This review provides an updated overview of the genetic predisposition and immunological mechanisms behind the pathogenesis of DILI and presents the state-of-the-art experimental models to study DILI at the pre-clinical level.

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Activation and transcriptional profile of monocytes and CD8+ T cells are altered in checkpoint inhibitor-related hepatitis

Cited by 41 publications

References 49 publications

Biological Bases of Immune-Related Adverse Events and Potential Crosslinks With Immunogenic Effects of Radiation

Biological Bases of Immune-Related Adverse Events and Potential Crosslinks With Immunogenic Effects of Radiation

Mechanisms of immune checkpoint inhibitor-mediated liver injury

Immune-Mediated Drug-Induced Liver Injury: Immunogenetics and Experimental Models

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