Kinetics of IFNγ-Induced Cytokines and Development of Immune-Related Adverse Events in Patients Receiving PD-(L)1 Inhibitors
Alserawan, Leticia (Institut de Recerca Sant Pau)
Mulet Gual, Maria (Institut de Recerca Sant Pau)
Anguera, Georgia (Institut de Recerca Sant Pau)
Riudavets, Mariona (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Zamora, Carlos (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Osuna Gómez, Rubén (Institut de Recerca Sant Pau)
Serra, Jorgina (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Barba Joaquin, Andrés (Institut de Recerca Sant Pau)
Sullivan, Ivana (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Majem, Margarita (Institut de Recerca Sant Pau)
Vidal, Silvia (Institut de Recerca Sant Pau)
Universitat Autònoma de Barcelona

Fecha:	2024
Resumen:	Immune checkpoint inhibitors (ICI) have the potential to trigger unpredictable immune-related adverse events (irAEs), which can be severe. The underlying mechanisms of these events are not fully understood. As PD-L1 is upregulated by IFN, the heightened immune activation resulting from PD-1/PD-L1 inhibition may enhance the IFN response, triggering the expression of IFN-inducible genes and contributing to irAE development and its severity. In this study, we investigated the interplay between irAEs and the expression of IFN-inducible chemokines and cytokines in 134 consecutive patients with solid tumours treated with PD-(L)1 inhibitors as monotherapy or in combination with chemotherapy or other immunotherapy agents. We compared the plasma levels of IFN-associated cytokines (CXCL9/10/11, IL-18, IL-10, IL-6 and TGFβ) at various time points (at baseline, at the onset of irAE and previous to irAE onset) in three patient groups categorized by irAE development and severity: patients with serious irAEs, mild irAEs and without irAEs after PD-(L)1 inhibitors. No differences were observed between groups at baseline. However, patients with serious irAEs exhibited significant increases in CXCL9/10/11, IL-18 and IL-10 levels at the onset of the irAE compared to baseline. A network analysis and correlation patterns highlighted a robust relationship among these chemokines and cytokines at serious-irAE onset. Combining all of the analysed proteins in a cluster analysis, we identified a subgroup of patients with a higher incidence of serious irAEs affecting different organs or systems. Finally, an ROC analysis and a decision tree model proposed IL-18 levels ≥ 807 pg/mL and TGFβ levels ≤ 114 pg/mL as predictors for serious irAEs in 90% of cases. In conclusion, our study elucidates the dynamic changes in cytokine profiles associated with serious irAE development during treatment with PD-(L)1 inhibitors. The study's findings offer valuable insights into the intricate IFN-induced immune responses associated with irAEs and propose potential predictive markers for their severity.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Anti-pd-(l)1 inhibitors ; Cytokines ; Immune checkpoint inhibitors ; Immune-related adverse events (irAEs) ; Interferon ; Predictive biomarkers
Publicado en:	Cancers, Vol. 16 Núm. 9 (may 2024) , p. 1759, ISSN 2072-6694

DOI: 10.3390/cancers16091759
PMID: 38730712

16 p, 2.4 MB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut de Recerca Sant Pau
Artículos > Artículos de investigación
Artículos > Artículos publicados