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Toxicity-specific peripheral blood T and B cell dynamics in anti-PD-1 and combined immune checkpoint inhibition.
- Source :
- Cancer Immunology, Immunotherapy; Dec2023, Vol. 72 Issue 12, p4049-4064, 16p
- Publication Year :
- 2023
-
Abstract
- Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape of advanced malignancies, but come with a diverse spectrum of immune-related adverse events (irAEs). Mechanistic studies can aid the transition from expert-opinion to evidence-based irAE treatment strategies. We aimed to longitudinally characterize peripheral blood T and B cell dynamics in ICI-treated patients by multicolor flow cytometry and serum multiplex immunoassay at baseline, ± 3 weeks and ± 6 weeks or upon clinically relevant irAEs. We analyzed samples from 44 ICI-treated patients (24 anti-PD-1 monotherapy, 20 combined anti-PD-1/anti-CTLA-4; cICI), of whom 21 developed irAEs, and 10 healthy donors. IrAEs after cICI were characterized by significantly enhanced proliferation of Th1-associated, mainly (CD4<superscript>+</superscript>) CD27<superscript>−</superscript> effector memory T cells, as well as Th17-associated immune responses and germinal center activation (reflected by CXCL13 and IL-21 increases). We observed no changes in CD21<superscript>lo</superscript>, memory, class-switched or newly activated B cell subsets. Particularly double-positive PD-1<superscript>+</superscript>LAG-3<superscript>+</superscript> CD8<superscript>+</superscript> T cells showed enhanced cytotoxic capacity in patients with irAEs after cICI. Within anti-PD-1 monotherapy, irAEs were associated with modestly enhanced Th1-associated responses reflected by increased serum CXCL9 and CXCL10. In conclusion, ICI-induced toxicity is dominated by enhanced Th1-associated responses, but in cICI we also found evidence for Th17-associated responses and germinal center activation. Together, our data add to the growing body of evidence that irAEs may be driven by newly activated CD4<superscript>+</superscript> helper T cells, specifically after cICI. This study also supports tailored irAE treatment, based on ICI regimen, and to deploy specific strategies such as Th17 inhibition especially in cICI-associated irAEs. [ABSTRACT FROM AUTHOR]
- Subjects :
- IMMUNE checkpoint inhibitors
B cells
T cells
T helper cells
DRUG side effects
Subjects
Details
- Language :
- English
- ISSN :
- 03407004
- Volume :
- 72
- Issue :
- 12
- Database :
- Complementary Index
- Journal :
- Cancer Immunology, Immunotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 174029074
- Full Text :
- https://doi.org/10.1007/s00262-023-03541-0