Modeling human pediatric and adult gliomas in immunocompetent mice through costimulatory blockade

Abstract

Currently, human glioma tumors are mostly modeled in immunodeficient recipients; however, lack of interactions with adaptive immune system is a serious flaw, particularly in the era when immunotherapies dominate treatment strategies. Our group was the first to successfully establish the orthotopic transplantation of human glioblastoma (GBM) in immunocompetent mice by inducing immunological tolerance using a short-term, systemic costimulation blockade strategy (CTLA-4-Ig and MR1). In this study, we further validated the feasibility of this method by modeling pediatric diffuse intrinsic pontine glioma (DIPG) and two types of adult GBM (GBM1, GBM551), in mice with intact immune systems and immunodeficient mice. We found that all three glioma models were successfully established, with distinct difference in tumor growth patterns and morphologies, after orthotopic xenotransplantation in toleranceinduced immunocompetent mice. Long-lasting tolerance that is maintained for up to nearly 200 d in GBM551 confirmed the robustness of this model. Moreover, we found that tumors in immunocompetent mice displayed features more similar to the clinical pathophysiology found in glioma patients, characterized by inflammatory infiltration and strong neovascularization, as compared with tumors in immunodeficient mice. In summary, we have validated the robustness of the costimulatory blockade strategy for tumor modeling and successfully established three human glioma models including the pediatric DIPG whose preclinical study is particularly thwarted by the lack of proper animal models.

A Signature of Nine lncRNA Methylated Genes Predicts Survival in Patients With Glioma

“…High malignancy and recurrence rates make glioma the most lethal primary brain tumor of the central nervous system ( 35 , 36 ). With the development of glioma mechanism research and clinical treatment, some prognostic factors have been well-characterized, including WHO grade, isocitrate dehydrogenase (IDH) status, and 1p/19q codeletion status.…”

Augmented Therapeutic Potential of Glutaminase Inhibitor CB839 in Glioblastoma Stem Cells Using Gold Nanoparticle Delivery

“…As has been well described in the literature for the study of GBM in vivo [ 60 , 61 , 62 , 63 ], we suggest a xenograft approach of human tumor stem cell models in rodent carriers, ideally in immune-tolerant models [ 64 ], to investigate the immune relevance of the applied intervention using nanocarried-CB839 in the future. Such an immunocompetent mouse model for human GBM cells—which has also been recently used for testing additional disease types [ 65 ]—would also help to study the effects of Au-CB839 NPs on the immune microenvironment of the tumor. Given the emergence of immune therapies as effective cancer treatments, the inclusion of such assays in future drug development projects are desirable to increase translational relevance.…”

From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders

“…Our recent study revealed that DMT and psilocin down‐regulate CD80 co‐stimulatory molecule expression on the surface of microglial cells, with and without LPS stimulation (Kozlowska, Klimczak, Wiatr et al, 2021). The co‐stimulatory signal is crucial for recruiting adaptive immune cells; therefore, blockade of co‐stimulatory molecules an attractive immunosuppressive strategy (Lan et al, 2020). The unique properties of psychedelics in suppressing inflammatory responses (Szabo et al, 2014; Flanagan & Nichols, 2018; Nardai et al, 2020), and promoting neural survival (Szabo et al, 2016) and plasticity (Ly et al, 2018), could be a strong rationale for the hypothesis that psychedelics might support grafted cells and facilitate their survival for therapeutic benefits.…”

“…Our recent study revealed that DMT and psilocin down-regulate CD80 co-stimulatory molecule expression on the surface of microglial cells, with and without LPS stimulation (Kozlowska, Klimczak, Wiatr et al, 2021). The co-stimulatory signal is crucial for recruiting adaptive immune cells; therefore, blockade of co-stimulatory molecules an attractive immunosuppressive strategy (Lan et al, 2020).…”