Journal article
Checkpoint inhibition reduces the threshold for Drug-Specific T-Cell priming and increases the incidence of sulfasalazine hypersensitivity
Toxicological Sciences, Vol.186(1), pp.58-69
2021
Abstract
An emerging clinical issue associated with immune-oncology agents is the collateral effects on the tolerability of concomitant medications. One report of this phenomenon was the increased incidence of hypersensitivity reactions observed in patients receiving concurrent immune checkpoint inhibitors (ICIs) and sulfasalazine (SLZ). Thus, the aim of this study was to characterize the T cells involved in the pathogenesis of such reactions, and recapitulate the effects of inhibitory checkpoint blockade on de-novo priming responses to compounds within in vitro platforms. A regulatory competent human dendritic cell/T-cell coculture assay was used to model the effects of ICIs on de novo nitroso sulfamethoxazole- and sulfapyridine (SP) (the sulfonamide component of SLZ) hydroxylamine-specific priming responses. The role of T cells in the pathogenesis of the observed reactions was explored in 3 patients through phenotypic characterization of SP/sulfapyridine hydroxylamine (SPHA)-responsive T-cell clones (TCC), and assessment of cross-reactivity and pathways of T-cell activation. Augmentation of the frequency of responding drug-specific T cells and intensity of the T-cell response was observed with PD-1/PD-L1 blockade. Monoclonal populations of SP- and SPHA-responsive T cells were isolated from all 3 patients. A core secretory effector molecule profile (IFN-γ, IL-13, granzyme B, and perforin) was identified for SP and SPHA-responsive TCC, which proceeded through Pi and hapten mechanisms, respectively. Data presented herein provides evidence that drug-responsive T cells are effectors of hypersensitivity reactions observed in oncology patients administered ICIs and SLZ. Perturbation of drug-specific T-cell priming is a plausible explanation for clinical observations of how an increased incidence of these adverse events is occurring.
Details
- Title
- Checkpoint inhibition reduces the threshold for Drug-Specific T-Cell priming and increases the incidence of sulfasalazine hypersensitivity
- Authors/Creators
- S. Hammond (Author/Creator) - University of LiverpoolA. Olsson-Brown (Author/Creator) - University of LiverpoolS. Grice (Author/Creator) - University of LiverpoolA. Gibson (Author/Creator) - Murdoch UniversityJ. Gardner (Author/Creator) - University of LiverpoolJ.L. Castrejón-Flores (Author/Creator) - Instituto Politécnico NacionalC. Jolly (Author/Creator) - University of LiverpoolB.A. Fisher (Author/Creator) - University of BirminghamN. Steven (Author/Creator) - University Hospitals Birmingham NHS Foundation TrustC. Betts (Author/Creator) - AstraZeneca (United Kingdom)M. Pirmohamed (Author/Creator) - University of LiverpoolX. Meng (Author/Creator) - University of LiverpoolD.J. Naisbitt (Author/Creator) - University of Liverpool
- Publication Details
- Toxicological Sciences, Vol.186(1), pp.58-69
- Publisher
- Oxford Academic
- Identifiers
- 991005540695107891
- Copyright
- © 2022 The Authors.
- Murdoch Affiliation
- Institute for Immunology and Infectious Diseases
- Language
- English
- Resource Type
- Journal article
UN Sustainable Development Goals (SDGs)
This output has contributed to the advancement of the following goals:
Source: InCites
Metrics
25 File views/ downloads
31 Record Views
InCites Highlights
These are selected metrics from InCites Benchmarking & Analytics tool, related to this output
- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.265 Dermatology - Skin Allergies
- 1.265.1140 Drug Hypersensitivity
- Web Of Science research areas
- Toxicology
- ESI research areas
- Pharmacology & Toxicology