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ALL the comforts of homing: lymphoblasts find cerebrospinal fluid inhospitable without meningeal cell contact

2020; Wiley; Volume: 189; Issue: 3 Linguagem: Inglês

10.1111/bjh.16368

1365-2141

Antigoni Manousopoulou, Leo D. Wang,

Lung Cancer Research Studies

The central nervous system (CNS) is an important sanctuary site in acute lymphoblastic leukaemia (ALL), and CNS involvement has important prognostic and therapeutic implications. Children with CNS involvement at diagnosis have a poorer prognosis, and even with CNS-directed therapies, ~2 to 8% of paediatric patients relapse in the CNS (Pui et al., 2009). In adults, even with aggressive therapies such as stem cell transplantation, CNS involvement at any time increases risk of CNS relapse and portends worse overall outcomes (Fielding et al., 2007; Aldoss et al., 2016). Many mechanisms contribute to the uniquely important role of the CNS in ALL. The blood–brain barrier (BBB), blood–leptomeningeal barrier (BLMB), and blood–cerebrospinal fluid (CSF) barrier (BCSFB) constitute partial barriers to systemically-administered therapies (Frishman-Levy & Izraeli, 2017), which helps to shield CNS disease. It has also long been known that CNS ALL is predominantly a leptomeningeal disease (Price & Johnson, 1973), a fact that has often been interpreted as reflecting mechanisms of CNS invasion (Williams et al., 2016; Münch et al., 2017; Yao et al., 2018). However, it is becoming clear that factors promoting ALL survival and chemoresistance once it has entered the CNS are probably more important than mechanisms of entry into the CNS (Akers et al., 2011; Krause et al., 2015; Gaynes et al., 2017), suggesting that a biologically and clinically significant bona fide CNS niche exists for ALL. Niches are, by definition, complex functional support structures that provide myriad inputs to support the growth and survival of particular cell types. They typically incorporate numerous cell types, soluble factors, and extracellular matrix components along with physical characteristics such as oxygen tension, pH, and temperature (Wang & Wagers, 2011). Consequently, niches can be difficult to characterize, and even more difficult to address therapeutically. Identifying critical niche components is a crucial first step in developing strategies to target them. In the CNS, both cellular and acellular niche components have been identified for ALL. The extracellular matrix protein laminin appears to be required for entry of lymphoblasts into the CNS (Yao et al., 2018). After entry, several CNS stromal cell types are capable of supporting and promoting ALL survival (Akers et al., 2011; Gaynes et al., 2017); this is partly through the expression of membrane proteins such as vascular cell adhesion protein 1 (VCAM1) (Hall et al., 2004) and the elaboration of soluble factors such as interleukins 15 (IL-15) and 7 (IL-7) (Lee et al., 1996; Michaelson et al., 1996). In addition to serving as ALL growth and survival factors, both IL-15 and IL-7 expression also predict CNS involvement (Williams et al., 2014; Alsadeq et al., 2018). In this issue of the British Journal of Haematology, Brasile et al. somewhat surprisingly discover that CSF is toxic to ALL cells. In addition to substantial decreases in proliferation and viability, B- (NALM-6) and T- (Jurkat) ALL cell lines cultured in CSF manifest increased in reactive oxygen species (ROS) as well as increased apoptotic priming; significantly, this phenomenon is only partially compensated for by supplementation of CSF with fetal bovine serum. These results argue strongly that soluble factors in CSF are directly toxic to ALL cells. Most other studies of the CNS niche have been done using conventional cell culture media in vitro, so this novel finding is a valuable addition to our understanding of the CNS niche. These data beg the question of what specific factors compensate for CSF toxicity in the CNS niche, and the authors confirm that meningeal cells are protective of B- and T-lymphoblasts in a contact-dependent manner. They report that leukaemia cell lines and primary B- and T-ALL cells cocultured in CSF with primary human meningeal cells (purchased commercially and defined as FN+, GFAP-, ASMA-, and Thy1·1-) retain their viability and low levels of ROS. In keeping with other published studies (Akers et al., 2011), this protective effect is dependent on direct cell–cell contact; abrogating cellular adhesion using CXCR4 inhibitor, ICAM-1/E-selectin inhibitor, or a transwell system eliminates the benefit of coculture. These intriguing results may help to explain why the preponderance of CNS ALL is leptomeningeal, rather than parenchymal. Additionally, this suggests a therapeutic strategy for treating CNS leukaemia; driving cells out of the meningeal niche and into the hostile environment of the CSF may suffice to erase any protection afforded to leukaemia cells by the CNS. However, much still remains to be done. In the bone marrow leukaemia niche, which is currently better characterized than the CNS leukaemia niche, leukaemia-propagating cells secrete factors to recruit and modify bone marrow mesenchymal stem cells, creating a more hospitable niche (Duan et al., 2014). It would be interesting to determine whether similar crosstalk exists between leukaemia cells and meningeal, choroid plexus, or other CNS niche cells. Additionally, this finding may have applications in fields such as adoptive immunotherapy. Brain-tumour-targeted chimeric antigen receptor (CAR) T cells are believed to be more effective against leptomeningeal disease than parenchymal disease, and preclinical studies show that CAR T cells are better able to control systemic disease when injected intraventricularly as opposed to intravenously, even in the absence of intracranial disease (X. Wang, personal communication). If meningeal cells are capable of supporting the survival and quiescence of adoptively transferred engineered T cells, it is likely that CAR T cells can also take advantage of this CNS niche for optimum efficacy. The authors wish to thank Xiuli Wang, Christine Brown, Alex Kentsis, and Alejandro Gutierrez for thoughtful discussion and helpful suggestions. AM and LDW wrote and edited the manuscript. The authors report no conflicts of interest relevant to this publication. LDW is supported by NCI K08CA201591 and has funding from the Margaret E. Early Medical Research Trust, The Gabrielle’s Angel Foundation, the Hyundai Hope on Wheels Foundation, and the B + Foundation.