Immune mechanisms of toxicity from checkpoint inhibitors

Trends in cancer, Journal Year: 2023, Volume and Issue: 9(7), P. 543 - 553

Published: April 27, 2023

Immunotherapy has changed the treatment landscape for cancer over past decade. Inhibitors of immune checkpoint proteins cytotoxic T lymphocyte antigen (CTLA)-4, programmed death (PD)-1, and PD ligand 1 (PD-L1) can induce durable remissions in a subset patients with metastatic disease. However, these treatments be limited by inflammatory toxicities that affect any organ system body some cases life threatening. Considerable progress been made understanding drivers as well effective management strategies. Further research into molecular cellular mechanisms drive toxicity will enable better prediction development optimized therapies avoid interfering antitumor immunity. In this review, we discuss our current from inhibitors (ICIs) propose optimal strategies toxicities.

Language: Английский

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Microbiota-dependent activation of CD4 ⁺ T cells induces CTLA-4 blockade–associated colitis via Fcγ receptors

Science, Journal Year: 2024, Volume and Issue: 383(6678), P. 62 - 70

Published: Jan. 4, 2024

Immune checkpoint inhibitors can stimulate antitumor immunity but also induce toxicities termed immune-related adverse events (irAEs). Colitis is a common and severe irAE that lead to treatment discontinuation. Mechanistic understanding of gut irAEs has been hampered because robust colitis not observed in laboratory mice treated with inhibitors. We report here this limitation be overcome by using harboring the microbiota wild-caught mice, which develop overt following anti-CTLA-4 antibodies. Intestinal inflammation driven unrestrained activation IFNγ-producing CD4 + T cells depletion peripherally induced regulatory through Fcγ receptor signaling. Accordingly, nanobodies lack an Fc domain promote responses without triggering colitis. This work suggests strategy for mitigating while preserving stimulating effects CTLA-4 blockade.

Language: Английский

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In vivo dendritic cell reprogramming for cancer immunotherapy

Science, Journal Year: 2024, Volume and Issue: 386(6719)

Published: Sept. 5, 2024

Immunotherapy can lead to long-term survival for some cancer patients, yet generalized success has been hampered by insufficient antigen presentation and exclusion of immunogenic cells from the tumor microenvironment. Here, we developed an approach reprogram in vivo adenoviral delivery transcription factors PU.1, IRF8, BATF3, which enabled them present antigens as type 1 conventional dendritic cells. Reprogrammed remodeled their microenvironment, recruited, expanded polyclonal cytotoxic T cells; induced regressions; established systemic immunity multiple mouse melanoma models. In human spheroids xenografts, reprogramming dendritic-like progressed independently immunosuppression, usually limits immunotherapy. Our study paves way clinical trials immune cell

Language: Английский

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Functional differences between rodent and human PD-1 linked to evolutionary divergence

Science Immunology, Journal Year: 2025, Volume and Issue: 10(103)

Published: Jan. 3, 2025

Mechanistic understanding of the inhibitory immunoreceptor PD-1 is largely based on mouse models, but human and share only 59.6% amino acid identity. Here, we found that more than PD-1, owing to stronger interactions with ligands PD-L1 PD-L2 efficient recruitment effector phosphatase Shp2. In a melanoma model adoptively transferred T cells, humanization intracellular domain disrupted antitumor activity CD8

Language: Английский

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Cardiac myosin-specific autoimmune T cells contribute to immune-checkpoint-inhibitor-associated myocarditis

Cell Reports, Journal Year: 2022, Volume and Issue: 41(6), P. 111611 - 111611

Published: Nov. 1, 2022

Immune checkpoint inhibitors (ICIs) are an effective therapy for various cancers; however, they can induce immune-related adverse events (irAEs) as a side effect. Myocarditis is uncommon, but fatal, irAE caused after ICI treatments. Currently, the mechanism of ICI-associated myocarditis unclear. Here, we show development in A/J mice induced by anti-PD-1 monoclonal antibody (mAb) administration alone without tumor cell inoculation, immunization, or viral infection. Mice with have increased cardiac infiltration, elevated troponin levels, and arrhythmia. Anti-PD-1 mAb treatment also causes irAEs other organs. Autoimmune T cells recognizing myosin activated myocarditis. Notably, myosin-specific present naive mice, showing phenotype antigen-experienced cells. Collectively, establish clinically relevant mouse model find contribution to pathogenesis.

Language: Английский

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Checkpoint Inhibitor Pneumonitis Induced by Anti-PD-1/PD-L1 Therapy in Non-Small-Cell Lung Cancer: Occurrence and Mechanism

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: April 7, 2022

Immune checkpointty inhibitors (ICIs), particularly those targeting programmed death 1 (PD-1) and anti-programmed ligand (PD-L1), enhance the antitumor effect by restoring function of inhibited effector T cells produce durable responses in a large variety metastatic late patients with non-small-cell lung cancer. Although often well tolerated, activation immune system results side effects known as immune-related adverse events (irAEs), which can affect multiple organ systems, including lungs. The occurrence severe pulmonary irAEs, especially checkpoint inhibitor pneumonitis (CIP), is rare but has extremely high mortality overlaps respiratory symptoms imaging primary tumors. development CIP may be accompanied radiation pneumonia infectious pneumonia, leading to simultaneous mixture several types inflammation However, there lack authoritative diagnosis, grading criteria clarified mechanisms CIP. In this article, we review incidence median time onset cancer treated PD-1/PD-L1 blockade clinical studies. We also summarize features, potential mechanisms, management predictive biomarkers caused treatment.

Language: Английский

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Mechanisms of immune checkpoint inhibitor-mediated liver injury

Acta Pharmaceutica Sinica B, Journal Year: 2021, Volume and Issue: 11(12), P. 3727 - 3739

Published: Oct. 19, 2021

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 regulation tolerance. Recently checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, they come with the cost of related adverse events involving multiple organs such as liver. Due its constant exposure foreign antigens, liver has evolved a high capacity for tolerance, therefore, blockade checkpoints can result in aberrant activation affecting up 20% patients depending on agent(s) used underlying factors. This type hepatotoxicity is termed mediated injury from (ILICI) more common when CTLA4 PD-1/PD-L1 combination. mechanisms this unique not fully understood; contribution CD8

Language: Английский

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Inhibition of IL-17A Protects against Thyroid Immune-Related Adverse Events while Preserving Checkpoint Inhibitor Antitumor Efficacy

The Journal of Immunology, Journal Year: 2022, Volume and Issue: 209(4), P. 696 - 709

Published: July 14, 2022

Abstract Immune checkpoint inhibitor (ICI) immunotherapy leverages the body’s own immune system to attack cancer cells but leads unwanted autoimmune side effects in up 60% of patients. Such immune-related adverse events (IrAEs) may lead treatment interruption, permanent organ dysfunction, hospitalization, and premature death. Thyroiditis is one most common IrAEs, cause thyroid IrAEs remains unknown. In this study, we use a new, physiologically relevant mouse model ICI-associated autoimmunity identify key role for type 3 development IrAEs. Multiple lineages IL-17A–producing T expand tissue with ICI treatment. Intrathyroidal innate-like γδT17 were increased tumor-free mice, whereas adaptive Th17 also prominent tumor-bearing following Furthermore, Ab-based inhibition IL-17A, clinically available therapy, significantly reduced IrAE ICI-treated mice without tumor challenge. Finally, combination IL-17A neutralization multiple models did not reduce antitumor efficacy. These studies suggest that targeting cell function via axis impairing efficacy be generalizable strategy address immune-mediated

Language: Английский

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Clonally expanded, thyrotoxic effector CD8 ⁺ T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(696)

Published: May 17, 2023

Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) therapy for cancer and represents an increasing clinical challenge expanding the use these treatments. To date, human immunopathogenic studies immune-related adverse events (IRAEs) have relied on sampling circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from individuals ICI-thyroiditis, one most common IRAEs, compared infiltrates those spontaneous autoimmune Hashimoto’s thyroiditis (HT) or no disease. Single-cell RNA sequencing revealed a dominant, clonally expanded population thyroid-infiltrating cytotoxic CXCR6 + CD8 T (effector cells) present ICI-thyroiditis but not HT healthy controls. Furthermore, identified crucial role interleukin-21 (IL-21), cytokine secreted by intrathyroidal follicular (T FH ) helper PH cells, as driver thyrotoxic effector cells. In presence IL-21, acquired activated phenotype up-regulation molecules interferon-γ (IFN-γ) granzyme B, increased expression chemokine receptor CXCR6, capacity. We validated findings vivo using mouse model IRAEs further demonstrated that genetic deletion IL-21 signaling protected ICI-treated mice infiltration. Together, reveal mechanisms candidate therapeutic targets who develop IRAEs.

Language: Английский

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A yeast-based oral therapeutic delivers immune checkpoint inhibitors to reduce intestinal tumor burden

Cell chemical biology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Engineered probiotics are an emerging platform for in situ delivery of therapeutics to the gut. Herein, we developed orally administered, yeast-based therapeutic system deliver next-generation immune checkpoint inhibitor (ICI) proteins directly gastrointestinal tumors. We engineered Saccharomyces cerevisiae var. boulardii (Sb), a probiotic yeast with high genetic tractability and innate anticancer activity, secrete "miniature" antibody variants that target programmed death ligand 1 (Sb_haPD-1). When tested ICI-refractory colorectal cancer (CRC) mouse model, Sb_haPD-1 significantly reduced intestinal tumor burden resulted significant shifts cell profile microbiome composition. This oral is modular highly customizable, opening new avenues targeted drug can be applied treat myriad malignancies.

Language: Английский

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