Immune involvement of the contralateral hemisphere in a glioblastoma mouse model

Abstract

BackgroundGlioblastoma (GBM) is the most common and deadliest form of brain cancer in adults. Standard treatment, consisting of surgery and radiochemotherapy, only provides a modest survival benefit and is incapable of combating infiltrating GBM cells in other parts of the brain. New therapies in clinical trials, such as anti-programmed cell death 1 immunotherapy, have so far shown limited success in GBM. Moreover, it is unclear how the growth of GBM suppresses the immune system locally at the site of the brain tumor or if distant sites of tumor cell migration are also involved. Invasive GBM cells in brain tissue beyond the primary tumor limit the use of surgery, thus immunotherapy could be beneficial if activated/suppressed immune cells are present in the contralateral hemisphere.MethodsHere, we used a syngeneic orthotopic GL26 GBM mouse model and multiparameter fluorescence-activated cell sorting analysis to study the phenotype of resident and infiltrating immune cells in both the brain tumor hemisphere and contralateral hemisphere.ResultsWe show that lymphoid cells, including tumor antigen-specific CD8+tumor-infiltrating lymphocytes (TILs) are present in the tumor and are characterized by a tolerogenic phenotype based on high immune checkpoint expression. Massive infiltration of myeloid cells is observed, expressing immune checkpoint ligands, suggesting an immune-dependent coinhibitory axis limiting TIL responses. Surprisingly, these phenotypes are paralleled in the contralateral hemisphere, showing that infiltrating immune cells are also present at distant sites, expressing key immune checkpoints and immune checkpoint ligands.ConclusionWhole-brain analysis indicates active immune involvement throughout the brain, both at the site of the primary tumor and in the contralateral hemisphere. Using the right combination and timing, immune checkpoint blockade could have the potential to activate immune cells at the site of the brain tumor and at distant sites, thereby also targeting diffusely infiltrating GBM cells.

Glioma-associated microglia/macrophages augment tumorigenicity in canine astrocytoma, a naturally occurring model of human glioma

“…Increased microglial density has been observed in the contralateral normal-appearing cortical regions of rodent models 33 and human patients. 34 A positive relationship has been identified between the length of epilepsy history and microglia density in the cortex of human glioma patients.…”

Immunocompetent Mouse Models in the Search for Effective Immunotherapy in Glioblastoma

“…Although both models show a great histological resemblance, the main difference is that GL26 tumors show a large extent of necrosis and vascularity and therefore tend to be more hemorrhagic [116]. Crommentuijn et al [117] described the presence of a tumor antigen-specific CD8 + T cell population which displays a tolerogenic phenotype with a high expression of several immune checkpoints such as PD-1 and T cell immunoglobulin and ITIM domain (TIGIT). The infiltration of myeloid cells expressing these immune checkpoint ligands was also observed [117].…”

“…Crommentuijn et al [117] described the presence of a tumor antigen-specific CD8 + T cell population which displays a tolerogenic phenotype with a high expression of several immune checkpoints such as PD-1 and T cell immunoglobulin and ITIM domain (TIGIT). The infiltration of myeloid cells expressing these immune checkpoint ligands was also observed [117]. Furthermore, the importance of galactokinase (Gal1) in the immune suppression of the GL26 model was described, since it masks tumor cells from immune recognition [118,119].…”

“…GBM is strongly invasive and tumor cells can be found embedded in the normal parenchyma at great distance from the main tumor. This makes a complete resection not feasible [117]. Yadav et al analyzed this problem with the GL26 model, and they found that down regulation of C-X-C chemokine receptor type 4 (CXCR4) led to less perivascular invasion and increased survival.…”

Integrative Analysis of DNA Methylation and Transcriptome Identifies a Predictive Epigenetic Signature Associated With Immune Infiltration in Gliomas

“…At present, immune checkpoint inhibitors, such as anti-CTLA-4 monoclonal antibody (ipilimumab) and anti-PD-1 monoclonal antibody (nivolumab), have achieved good results in tumor therapy (O'Day et al, 2010;Rizvi et al, 2015). However, research on immune checkpoint inhibitors in glioma is still insufficient, and new drugs are currently being evaluated in animal models and in clinical trials (Omuro et al, 2018;Crommentuijn et al, 2020;Ladomersky et al, 2020).…”