AMD3100-mediated CXCR4 inhibition impairs development of primary lymphoma of the central nervous system

by Selleckchem | Jul 13 2023

A hallmark of primary lymphoma of the central nervous system (PCNSL, CNS) is the strong CXCR4 expression of the tumor cells, the function of which is still unknown. In vitro treatment of BAL17CNS lymphoma cells by AMD3100 which inhibits CXCR4-CXCL12 interactions resulted in the significantly differential expression of 273 genes encoding proteins involved in cell motility, cell-cell signaling and interaction, hematological system development and function, and immunological disease. Among the genes downregulated was the one encoding CD200, a regulator of CNS immunological activity. These data directly translated into the in vivo situation; BAL17CNS CD200 expression was downregulated by 89% (3% vs. 28% CD200+ lymphoma cells) in AMD3100-treated vs. untreated mice with BAL17CNS-induced PCNSL. Reduced lymphoma cell CD200 expression may contribute to the markedly increased microglial activation in AMD3100-treated mice. AMD3100 also maintained the structural integrity of blood-brain barrier tight junctions and the outer basal lamina of cerebral blood vessels. Subsequently, lymphoma cell invasion of the brain parenchyma was impaired and maximal parenchymal tumor size was significantly reduced by 82% in the induction phase. Thus, AMD3100 qualified as potentially attractive candidate to be included into the therapeutic concept of PCNSL. Beyond therapy, CXCR4-induced suppression of microglial activity is of general neuroimmunological interest and identifies CD200 expressed by the lymphoma cells as a novel mechanism of immune escape in PCNSL.

Comments:

Primary lymphoma of the central nervous system (PCNSL) is characterized by strong expression of CXCR4 in tumor cells, although the exact function of CXCR4 in this context is still not fully understood. A study using BAL17CNS lymphoma cells, which exhibit high CXCR4 expression, investigated the effects of inhibiting CXCR4-CXCL12 interactions with a drug called AMD3100.

In vitro treatment of BAL17CNS cells with AMD3100 resulted in significant changes in gene expression. Specifically, 273 genes involved in various cellular processes such as cell motility, cell-cell signaling and interaction, hematological system development and function, and immunological disease showed differential expression. Among the downregulated genes was CD200, which is known to regulate immunological activity in the central nervous system (CNS).

The in vivo experiments corroborated the in vitro findings. In mice with BAL17CNS-induced PCNSL that were treated with AMD3100, CD200 expression in lymphoma cells was downregulated by 89%. This decrease in CD200 expression was associated with increased microglial activation in the treated mice. Microglia are immune cells in the CNS that play a crucial role in immune surveillance and regulation. The reduced CD200 expression in lymphoma cells may contribute to enhanced microglial activity.

Furthermore, AMD3100 treatment helped maintain the structural integrity of tight junctions in the blood-brain barrier and the outer basal lamina of cerebral blood vessels. Consequently, lymphoma cell invasion of the brain parenchyma (the functional tissue of the brain) was impaired, resulting in a significant reduction (82%) in the maximal size of the parenchymal tumor during the induction phase.

Based on these findings, AMD3100 emerges as a potentially promising candidate for inclusion in the therapeutic approach to PCNSL. In addition to its therapeutic implications, the study also sheds light on the broader field of neuroimmunology by revealing that CXCR4-induced suppression of microglial activity is of general interest. The identification of CD200 expressed by lymphoma cells as a novel mechanism of immune escape in PCNSL adds to our understanding of the immune evasion strategies employed by cancer cells in the CNS.