The pathophysiology of neurological toxicities secondary to immune checkpoint inhibitors (ICIs) is unknown. Various mechanisms have been proposed: activation of cytotoxic CD8 T cells, autoantibodies via activation of B cells and CD4 cells, non-specific inflammation through the production of pro-inflammatory cytokines, and complement activation.
The aim of this research is to characterise the pathophysiological mechanisms of neurotoxicities in cancer patients treated with ICIs.
Adult patient (aged ≥ 18 years)
Affiliated with a social security scheme
Express consent to participate in the study
Indication for lumbar puncture And
Contraindication or refusal to perform a lumbar puncture
Sample not suitable for research (volume of CSF collected for treatment >5 mL)
Corticosteroid therapy or other immunomodulatory treatment in progress (discontinued less than 15 days prior to inclusion)
Pregnant or breastfeeding women
Parallel
Lumbar puncture and blood sampling
Other interventionFor all patients in the study, lumbar puncture will be performed as part of their care, according to the clinical indication given by the referring physician. If the patient gives their consent, an additional volume of CSF will be collected for this study, so that the total volume collected (care plus research) does not exceed 5 mL. No lumbar puncture will be performed specifically for the study. Blood samples will also be collected: these are additional blood tubes collected during a blood sample taken as part of the treatment (as described in the section 'Minimal risks and constraints added by the research').
Presence of nervous system-specific TCRs in CSF of patients with ICI-related neurotoxicity
Specific TCR repertoires of ICI-related neurotoxicity will be identified by TCR sequencing of CSF and blood lymphocytes of patients at the time of diagnosis of neurotoxicity of ICIs in comparison to those found in the control cohort 1.2. The target of these lymphocytes specifically found in cohort 1.1 will be assessed by EliSpot with known neuronal antigens as well as a search for serum and CSF onconeuronal autoantibodies. In silico methods as well as public TCR database will also be used to find the neurological targets.
Proportions of lymphocytes
Absolute number and percentage of different cells subsets in CSF (CD3, CD20, CD4, CD8, C56) and of their phenotype (naif, effector memory, central memory, Treg) and expression profile will be assessed in study cohort and control cohorts by single cell RNA sequencing and flow cytometry.
Concentration of pro and anti-inflammatory cytokines in CSF of patients with ICI-related neurotoxicity and control cohorts
Measurement of CSF cytokines concentration by Single-Molecule Array and comparison of their levels in the four cohorts. The comparaison of cohort 1.1 with control cohort 3 will allow us to determine the normal level of each cytokine, the comparaison with the other cohorts will lead to the identification of the specific cytokine profile of ICI-related neurotoixicity.
Presence and strength of correlation between TCR repertoires and phenotype/ expression profile of CSF lymphocytes and clinical presentation of ICI-related neurotoxicity
Comparison of the proportions of TCR repertoire, phenotypic and expression profiles of the lymphocytes present in the CSF between the subgroups of patients with different neurological presentations (encephalitis, myelitis, meningitis, polyraduculonevritis, neuropathy) within the cohort 1.1 by using Spearman correlation.
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