CSF Specific T Cell Activation Characterizes Neurological Immune-related Adverse Events Following Immune Checkpoint Inhibitor Therapy
Louisa Müller-Miny1, Svea Haessner1, Frederike Straeten1, Andreas Schulte-Mecklenbeck1, Heinz Wiendl2, Oliver Grauer1, Gerd Meyer zu Hörste1
1University Hospital Münster, 2University of Muenster
Objective:
We aimed to identify mechanisms of immune checkpoint inhibitor associated neurological immune related adverse events (irAE) by studying their immune cell composition.
Background:
While immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, they are associated with a severe risk of irAE. Neurological irAE (NirAE) often manifest as ICI associated polyneuropathy (ICI PNP) with rapidly progressive and severe sequelae similar to Guillain-Barré syndrome (GBS).
Design/Methods:
Using retrospective collection of flow cytometry data (n=43), we investigated the immune cell composition of paired cerebrospinal fluid (CSF) and blood NirAE samples of NirAEs, non-neurological irAEs and no irAE. We additionally stratified ICI PNP patients by flow cytometry and single cell sequencing and compared them to differential diagnosis such as confirmed tumor progression and Guillain-Barré Syndrome.
Results:
We detected a disease-specific cellular composition of CSF cells of NirAE patients. CSF specific T cells activation occurred only in NirAE patients but not in other irAE patients. A significant increase in CD4+ and CD8+ T cell activation can distinguish ICI PNP patients compared to GBS patients and provides first evidence of a possible discriminatory biomarker. Transcriptionally activated CD 8 T cells were more abundant in the CSF compared to control and showed an increase in cytotoxic differentially expressed genes.
Conclusions:
Strong T cell activation in the CSF only occurs when T cell-mediated irAE affect the nervous system. The organ specificity of ICI-autoimmunity may thus be determined also by the site of T cell disinhibition. This provides a clinically relevant biomarker that can distinguish ICI PNP from differential diagnosis and possibly guide further treatment decisions.