Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 23, 2023

Abstract Immune checkpoint inhibitors (CPIs) are a relatively newly licenced cancer treatment, which make once previously untreatable disease now amenable to potential cure. Combination regimens of anti-CTLA4 and anti-PD-1 show enhanced efficacy but prone off-target immune-mediated tissue injury, particularly at the barrier surfaces. To probe impact immune checkpoints on intestinal homoeostasis, mice challenged with immunotherapy manipulation microbiota. The profile colon these CPI-colitis is analysed using bulk RNA sequencing, single-cell sequencing flow cytometry. in dependent composition microbiota by induction lymphocytes expressing interferon-γ (IFNγ), cytotoxicity molecules other pro-inflammatory cytokines/chemokines. This pre-clinical model could be attenuated following blockade IL23/IFNγ axis. Therapeutic targeting IFNγ-producing or regulatory networks, may hold key reversing CPI-colitis.

Language: Английский

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Inhibition of IL-25/IL-17RA improves immune-related adverse events of checkpoint inhibitors and reveals antitumor activity

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(3), P. e008482 - e008482

Published: March 1, 2024

Background Immune checkpoint inhibitors (ICIs) have improved outcomes and extended patient survival in several tumor types. However, ICIs often induce immune-related adverse events (irAEs) that warrant therapy cessation, thereby limiting the overall effectiveness of this class therapeutic agents. Currently, available therapies used to treat irAEs might also blunt antitumor activity ICI themselves. Therefore, there is an urgent need identify treatments potential be administered alongside optimize their use. Methods Using a translationally relevant murine model anti-PD-1 anti-CTLA-4 antibodies-induced irAEs, we compared safety efficacy prednisolone, anti-IL-6, anti-TNFɑ, anti-IL-25 (IL-17E), anti-IL-17RA (the receptor for IL-25) administration prevent reduce size. Results While all interventions were adequate inhibit onset pneumonitis hepatitis, treatment with or antibodies exerted additional activity. Mechanistically, IL-25/IL-17RA blockade reduced number organ-infiltrating lymphocytes. Conclusion These findings suggest may serve as target when treating ICI-responsive tumors, allowing better control while suppressing toxicities.

Language: Английский

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Immune-mediated colitis after immune checkpoint inhibitor therapy

Trends in Molecular Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Immune checkpoint inhibitors (ICIs) have led to improved outcome in patients with various types of cancer. Due inhibition physiological anti-inflammatory mechanisms, treated ICIs may develop autoimmune inflammation the colon, associated morbidity, decreased quality life (QoL), and mortality. In this review, we summarize clinical pathophysiological aspects immune-mediated colitis (ImC), highlighting novel treatment options. trigger resident circulating T cell activation infiltration myeloid cells. addition, gut microbiota critically contribute intestinal immune dysregulation loss barrier function, thereby propagating local systemic inflammation. Currently available therapies for ImC include corticosteroids, antitumor necrosis factor-α (TNF-α)- anti-integrin α

Language: Английский

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Corticosteroid premedication on anti-tumor effect of immune checkpoint blockade in murine hepatocellular carcinoma models

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(2), P. e009704 - e009704

Published: Feb. 1, 2025

Corticosteroid is effective in alleviating immune-related adverse events (irAEs) of immune checkpoint blockade (ICB). However, prophylactic use corticosteroid to prevent irAEs not recommended due a looming concern that it may attenuate anti-tumor effect ICB. This study aims investigate whether premedication compromise efficacy dual ICB, regimen cause significant irAEs. Orthotopic BNL 1MEA.7R.1 and subcutaneous Hepa1-6 syngeneic hepatocellular carcinoma (HCC) models were used. Low-dose (LD; 10 µg) or high-dose (HD; 200 dexamethasone (Dexa) was intraperitoneally administered before each dose anti-CTLA-4 anti-PD-1. Tumor shrinkage, T cell priming, cytokine quantitation, as well cytotoxicity single-cell RNA-sequencing (scRNA-seq) tumor-infiltrating cells assessed. In the orthotopic model, (dICB) plus phosphate buffered saline (PBS) significantly reduced mean tumor weight (adjusted for SE) (0.73±0.18 g vs 2.45±0.54 g; p=0.03), while neither LD nor HD Dexa affected dICB-induced shrinkage. dICB PBS yielded complete response (CR) rate 100%, CR 85.7% (p>0.05, comparing PBS). ScRNA-seq analysis demonstrates did affect reduction major clusters exhausted CD4+ CD8+ but halved expansion effector memory cells. Nevertheless, premedication, regardless dosage, diminish production, does treatment murine HCC models. These results suggest clinical investigations corticosteroids alleviate severe be feasible.

Language: Английский

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In Vivo Evaluation of Pam₂Cys‐Modified Cancer‐Testis Antigens as Potential Self‐Adjuvanting Cancer Vaccines

Journal of Peptide Science, Journal Year: 2025, Volume and Issue: 31(6)

Published: May 6, 2025

ABSTRACT Peptide‐based vaccines, formulated with an appropriate adjuvant, offer a versatile platform for targeted cancer immunotherapy. While adjuvants are usually coadministered nucleic acid and protein synthetic peptide antigens afford more effective opportunity to covalently regioselectively graft immunostimulatory motifs directly onto the antigen scaffold yield self‐adjuvanting vaccines. Herein, we explore synthesis of two tissue‐restricted cancer‐testis (CTAs); New York oesophageal cell carcinoma 1 (NY‐ESO‐1) B melanoma 4 (BAGE4), both carrying toll‐like receptor (TLR) agonist, Pam 2 Cys. These constructs were evaluated in vivo along lipid nanoparticle (LNP) preparation underexplored BAGE4 antigen.

Language: Английский

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Recommendations for standardizing biopsy acquisition and histological assessment of immune checkpoint inhibitor-associated colitis

Journal for ImmunoTherapy of Cancer, Journal Year: 2022, Volume and Issue: 10(3), P. e004560 - e004560

Published: March 1, 2022

Immune checkpoint inhibitor-associated colitis (ICIC) affects approximately 15% of cancer patients treated with immunotherapy. Although histological evaluation is potentially valuable for both the diagnosis ICIC and disease activity, use in clinical practice heterogeneous. We aimed to develop expert recommendations standardize assessment activity ICIC. Using modified Research Development/University California Los Angeles (RAND/UCLA) appropriateness methodology, an international panel 11 pathologists rated 99 statements on a 9-point Likert scale during two rounds anonymous voting. Results were discussed between using moderated videoconferences. There are currently no disease-specific instruments assessing features The considered that colonoscopy at least three biopsies per segment from total five segments, including endoscopically normal inflamed areas, was appropriate tissue acquisition. They agreed should be oriented such long axis colonic crypts visualized stained hematoxylin eosin. Histological items voted evaluate included degree structural/architectural change, chronic inflammatory infiltrate, lamina propria intraepithelial neutrophils, crypt abscesses destruction, erosions/ulcerations, apoptosis, surface lymphocytosis, subepithelial collagen thickness. routine immunohistochemistry uncertain. These will help also identified development validation ICIC-specific index as research priority.

Language: Английский

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The Role of Myeloid Cells in Hepatotoxicity Related to Cancer Immunotherapy

Cancers, Journal Year: 2022, Volume and Issue: 14(8), P. 1913 - 1913

Published: April 10, 2022

Drug-related hepatotoxicity is an emerging clinical challenge with the widening use of immunotherapeutic agents in field oncology. This important complication to consider as more immune oncological targets are being identified show promising results trials. The application these therapeutics may be complicated by development immune-related adverse events (irAEs), a serious limitation often requiring high-dose immunosuppression and discontinuation cancer therapy. Hepatoxicity presents one most frequently encountered irAEs better understanding underlying mechanism crucial for alternative therapeutic interventions. As novel drug side effect, immunopathogenesis condition not completely understood. In liver, myeloid cells play central role maintenance homeostasis promotion inflammation. Recent research has associated hepatic various modulatory monoclonal antibodies. this review article, we provide overview pathogenesis during hepatoxicity related immunotherapies highlight potential treatment options.

Language: Английский

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Golden Syrian Hamster Models for Cancer Research

Cells, Journal Year: 2022, Volume and Issue: 11(15), P. 2395 - 2395

Published: Aug. 3, 2022

The golden Syrian hamster (

Language: Английский

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Emerging Next-Generation Target for Cancer Immunotherapy Research: The Orphan Nuclear Receptor NR2F6

Cancers, Journal Year: 2021, Volume and Issue: 13(11), P. 2600 - 2600

Published: May 26, 2021

Additional therapeutic targets suitable for boosting anti-tumor effector responses have been found inside CD4+ and CD8+ T cells. It is likely that future treatment options will combine surface receptor intracellular protein targets. Utilizing germline gene ablation as well CRISPR/Cas9-mediated acute mutagenesis, the nuclear NR2F6 (nuclear subfamily 2 group F member 6, also called Ear-2) has firmly characterized such an immune checkpoint in Targeting this appears to be a strategy improving immunotherapy responses, especially combination with CTLA-4 PD-1. Current preclinical experimental knowledge validates function of murine tumor models, which provides promising perspective regimens humans near future. While clinical focus remains on B7/CD28 family members, candidate are now being investigated laboratories around world R&D companies. Such alternative approach, if demonstrated successful, could supplement existing models significantly increase response rates cancer patients and/or expand reach therapy include wider range entities. In review, role emerging druggable target immuno-oncology research discussed, special emphasis unique potential its critical non-redundant both

Language: Английский

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Immune-mediated liver injury from checkpoint inhibitors: mechanisms, clinical characteristics and management

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 11, 2024

Language: Английский

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