Giguelay and Maschmeyer et al. detected only minor differences in the PBMC immune cell composition of 17 cancer patients receiving ICI therapy, 8 with and 9 without severe neurological immune-related adverse events (n-irAEs). The subset most enriched in those with ICI-induced n-irAEs was clonally-expanded, terminally-differentiated CD4+ CTLs with upregulated expression of genes associated with antigen activation, neuroinflammation and cell lysis. Of potential biomarkers previously linked to ICI-induced n-irAEs, the CXCL10 receptor CXCR3 was upregulated in PBMC, but the frequency of the most expanded CD8+ T cell subset, (TEM cells) was not.
Contributed by Paula Hochman
Background: Immune checkpoint inhibitor (ICI) therapies present a pillar of modern cancer therapy but can cause neurological immune-related adverse events (n-irAEs), of which up to 35% are severe or even fatal. However, the detailed immunological mechanisms and risk factors underlying n-irAEs remain largely unknown. Here, we leveraged single-cell genomics to dissect immune cell type, state, and clonal heterogeneity associated with n-irAEs.
Methods: We performed coupled single-cell RNA sequencing and T cell receptor (TCR) profiling on peripheral blood cells of 17 patients with cancer receiving ICI therapy, including 8 patients with acute neurotoxicity. This approach enabled integrated analyses of immune cell states and T cell clonality linked to ICI-induced n-irAEs.
Results: We profiled 186 435 immune cells and conducted pseudotime analyses, revealing that patients with n-irAEs, compared with controls, present with clonally expanded CD4+ cytotoxic T lymphocytes (CD4+ CTLs) with an n-irAE-specific effector gene expression profile. These T cells predominantly belong to a select set of expanded clonal families and express genes linked to antigen-induced activation, cell lysis, and neuroinflammation. Moreover, they highly express CXCR3 (FC=2.03 compared with control CD4+ CTLs, with a false discovery rate=7.7×10⁻⁴), encoding the chemokine receptor of CXCL10, previously nominated as a biomarker for severe ICI therapy-induced n-irAEs with concomitant multiple organ system toxicity.
Conclusions: Overall, our study highlights the expansion and activation of CD4+ CTLs in ICI-induced neurotoxicity, proposing these cells as potential targets for developing new biomarkers and therapeutic strategies to improve patient outcomes.
Author Info: (1) Berlin Institute of Health at Charit - Universittsmedizin Berlin, Berlin, Germany. Max-Delbrck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Insti
Author Info: (1) Berlin Institute of Health at Charit - Universittsmedizin Berlin, Berlin, Germany. Max-Delbrck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany. (2) Berlin Institute of Health at Charit - Universittsmedizin Berlin, Berlin, Germany. Max-Delbrck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany. Institute for Systemic Inflammation Research (ISEF), University of Lbeck, Lbeck, Germany. (3) Berlin Institute of Health at Charit - Universittsmedizin Berlin, Berlin, Germany. Department of Neurology with Experimental Neurology, Charit - Universittsmedizin Berlin, Berlin, Germany. (4) Berlin Institute of Health at Charit - Universittsmedizin Berlin, Berlin, Germany. Department of Neurology with Experimental Neurology, Charit - Universittsmedizin Berlin, Berlin, Germany. (5) Berlin Institute of Health at Charit - Universittsmedizin Berlin, Berlin, Germany. Department of Neurology with Experimental Neurology, Charit - Universittsmedizin Berlin, Berlin, Germany. Einstein Center for Neurosciences Berlin (ECN) at Charit - Universittsmedizin Berlin, Berlin, Germany. (6) Berlin Institute of Health at Charit - Universittsmedizin Berlin, Berlin, Germany. Max-Delbrck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany. (7) Berlin Institute of Health at Charit - Universittsmedizin Berlin, Berlin, Germany. Max-Delbrck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany. Department of Biology, Chemistry, Pharmacy, Freie Universitt Berlin, Berlin, Germany. Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA. (8) Berlin Institute of Health at Charit - Universittsmedizin Berlin, Berlin, Germany. Department of Neurology with Experimental Neurology, Charit - Universittsmedizin Berlin, Berlin, Germany. NeuroCure Cluster of Excellence, Charit Universittsmedizin Berlin, Berlin, Germany. (9) Berlin Institute of Health at Charit - Universittsmedizin Berlin, Berlin, Germany. Department of Neurology with Experimental Neurology, Charit - Universittsmedizin Berlin, Berlin, Germany. NeuroCure Cluster of Excellence, Charit Universittsmedizin Berlin, Berlin, Germany. (10) Berlin Institute of Health at Charit - Universittsmedizin Berlin, Berlin, Germany. Department of Neurology with Experimental Neurology, Charit - Universittsmedizin Berlin, Berlin, Germany. NeuroCure Cluster of Excellence, Charit Universittsmedizin Berlin, Berlin, Germany. Charit Universittsmedizin Berlin, Center for Stroke Research Berlin, Berlin, Germany. German Center for Neurodegenerative Diseases (DZNE), partner site Berlin, Berlin, Germany. German Centre for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany. German Center for Mental Health (DZPG), partner site Berlin, Berlin, Germany. (11) Berlin Institute of Health at Charit - Universittsmedizin Berlin, Berlin, Germany leif.ludwig@bih-charite.de samuel.knauss@charite.de. Department of Neurology with Experimental Neurology, Charit - Universittsmedizin Berlin, Berlin, Germany. (12) Berlin Institute of Health at Charit - Universittsmedizin Berlin, Berlin, Germany leif.ludwig@bih-charite.de samuel.knauss@charite.de. Max-Delbrck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany.
