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Adaptive and Innate Immune Responses in Multiple Sclerosis with 2 Anti-CD20 Therapy: Gene Expression and Protein Profiles

ABSTRACT: Transcriptome analysis of RNA samples from human PBMCs of anti-CD20 therapy in multiple sclerosis patients. Anti-CD20 is a highly effective therapy for multiple sclerosis (MS), a disease with multiple abnormalities in function of B and T cells and innate immune cells. Anti-CD20 therapy depletes B cells, which alters antibody production and has diverse effects on B cell immunity. These changes potentially affect immunity beyond B cells in MS. We determined if anti-CD20 therapy effects non-B-cell, as well as B-cell, gene expression and serum protein levels. We found anti-CD20 therapy reduced expression of 413 total genes and 185 B-cell-regulated genes at 2 weeks vs. pre-therapy. Expression of 19 (15%) of these B cell genes returned towards baseline by 6 months, including genes for the B cell activation protein, CD79A, and for immunoglobulin A, D, and G heavy chains. Expression pathways for Th17 and CD4 regulatory T cell (Treg) development, differentiation, and proliferation also quieted. In contrast, expression increased in Th1 and myeloid cell antiviral, pro-inflammatory, and toll-like receptor (TLR) gene pathways.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228330 | GEO | 2023/04/05

REPOSITORIES: GEO

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Project description:Background: Mutant BRAF targeted therapies remain a standard of care for the treatment of metastatic malignant melanoma (MM); however high initial response rates are tempered by the persistence of residual MM cells that eventually lead to disease recurrence and mortality. Since MM recurrence during targeted therapy can present with the simultaneous occurrence of multiple tumour nodules at the original body sites, we hypothesised the presence of an intrinsically resistant MM cell sub-population. Objectives: Identify an MM cell subpopulation that is intrinsically resistant to targeted therapy and so may be responsible for MM recurrence. Methods: Using melanoma cell lines, we define culture conditions for reproducible 3D growth of melanospheres to investigate putative cancer stem cell populations. We undertook RNA sequencing and bioinformatic analysis to characterise cell populations between adherent and non-adherent culture, and cells expressing or not expressing CD20. Furthermore, we define an in vitro assay to evaluate killing of melanoma cancer stem cells as a therapeutic test using combination therapies targeting driver mutation and CD20 marker. Results: We have described culture conditions that promote MM cells to form melanospheres with a reproducible colony forming efficiency of 0.3% to 1.3%. RNA sequencing of melanosphere versus conventional MM cell cultures (n=6), irrespective of the BRAF mutation status, showed that melanosphere formation was associated with growth and differentiation transcriptional signatures resembling MM tumours. Importantly, melanosphere formation also led to the emergence of a CD20+ MM cell subpopulation, similar to that observed in primary human MM tumours. CD20+ MM cells were resistant to BRAF inhibitor therapy, and consistent with this finding demonstrated a Forkhead box protein M1 (FOXM1) transcriptomic profile (n=6). Combining BRAF inhibitor and anti-CD20 antibody treatment led to the additional killing of previously resistant CD20+ BRAF mutant MM cells. Conclusions: In MM patients that harbour a CD20+ sub-population, combined therapy with BRAF inhibitor and anti-CD20 antibody could potentially kill residual MM cells and so prevent disease recurrence.

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Adaptive and Innate Immune Responses in Multiple Sclerosis with 2 Anti-CD20 Therapy: Gene Expression and Protein Profiles

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