Immune signatures of checkpoint inhibitor-induced autoimmunity-A focus on neurotoxicity.
Müller-Jensen L, Schulz AR, Mei HE, Mohr R, Ulrich C, Knape P, Frost N, Frischbutter S, Kunkel D, Schinke C, Ginesta Roque L, Maierhof SK, Nickel F, Heinzerling L, Endres M, Boehmerle W, Huehnchen P, Knauss S (2024)
Publication Type: Journal article
Publication year: 2024
Journal
Book Volume: 26
Pages Range: 279-294
Journal Issue: 2
Abstract
BACKGROUND: Neurologic immune-related adverse events (irAE-n) are rare but severe toxicities of immune checkpoint inhibitor (ICI) treatment. To overcome diagnostic and therapeutic challenges, a better mechanistic understanding of irAE-n is paramount. METHODS: In this observational cohort study, we collected serum and peripheral blood samples from 34 consecutive cancer patients with irAE-n (during acute illness) and 49 cancer control patients without irAE-n (pre- and on-ICI treatment, n = 44 without high-grade irAEs, n = 5 with high-grade nonneurologic irAEs). Patients received either anti-programmed cell death protein (PD)-1 or anti-PD ligand-1 monotherapy or anti-PD-1/anti-cytotoxic T-lymphocyte-associated protein-4 combination therapy. Most common cancers were melanoma, lung cancer, and hepatocellular carcinoma. Peripheral blood immune profiling was performed using 48-marker single-cell mass cytometry and a multiplex cytokine assay. RESULTS: During acute illness, patients with irAE-n presented higher frequencies of cluster of differentiation (CD)8+ effector memory type (EM-)1 and central memory (CM) T cells compared to controls without irAEs. Multiorgan immunotoxicities (neurologic + nonneurologic) were associated with higher CD8+ EM1 T cell counts. While there were no B cell changes in the overall cohort, we detected a marked decrease of IgD- CD11c+ CD21low and IgD- CD24+ CD21high B cells in a subgroup of patients with autoantibody-positive irAE-n. We further identified signatures indicative of enhanced chemotaxis and inflammation in irAE-n patients and discovered C-X-C motif chemokine ligand (CXCL)10 as a promising marker to diagnose high-grade immunotoxicities such as irAE-n. CONCLUSIONS: We demonstrate profound and partly subgroup-specific immune cell dysregulation in irAE-n patients, which may guide future biomarker development and targeted treatment approaches.
Authors with CRIS profile
Involved external institutions
Charité - Universitätsmedizin Berlin
Germany (DE)
Deutsches Rheuma-Forschungszentrum (DRFZ)
Germany (DE)
Berliner Institut für Gesundheitsforschung (BIH)
Germany (DE)
Klinikum der Universität München
Germany (DE)
Germany (DE)
Deutsches Rheuma-Forschungszentrum (DRFZ)
Germany (DE)
Berliner Institut für Gesundheitsforschung (BIH)
Germany (DE)
Klinikum der Universität München
Germany (DE)
How to cite
APA:
Müller-Jensen, L., Schulz, A.R., Mei, H.E., Mohr, R., Ulrich, C., Knape, P.,... Knauss, S. (2024). Immune signatures of checkpoint inhibitor-induced autoimmunity-A focus on neurotoxicity. Neuro-Oncology, 26(2), 279-294. https://doi.org/10.1093/neuonc/noad198
MLA:
Müller-Jensen, Leonie, et al. "Immune signatures of checkpoint inhibitor-induced autoimmunity-A focus on neurotoxicity." Neuro-Oncology 26.2 (2024): 279-294.
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