ERK1 as a Therapeutic Target for Dendritic Cell Vaccination against High-Grade Gliomas

Abstract

Glioma regression requires the recruitment of potent antitumor immune cells into the tumor microenvironment. Dendritic cells (DC) play a role in immune responses to these tumors. The fact that DC vaccines do not effectively combat high-grade gliomas, however, suggests that DCs need to be genetically modified specifically to promote their migration to tumor relevant sites. Previously, we identified extracellular signal-regulated kinase (ERK1) as a regulator of DC immunogenicity and brain autoimmunity. In the current study, we made use of modern magnetic resonance methods to study the role of ERK1 in regulating DC migration and tumor progression in a model of high-grade glioma. We found that ERK1-deficient mice are more resistant to the development of gliomas, and tumor growth in these mice is accompanied by a higher infiltration of leukocytes. ERK1-deficient DCs exhibit an increase in migration that is associated with sustained Cdc42 activation and increased expression of actin-associated cytoskeleton-organizing proteins. We also demonstrated that ERK1 deletion potentiates DC vaccination and provides a survival advantage in high-grade gliomas. Considering the therapeutic significance of these results, we propose ERK1-deleted DC vaccines as an additional means of eradicating resilient tumor cells and preventing tumor recurrence.

Fluorine-19 MRI for detection and quantification of immune cell therapy for cancer

“…In a different study, PFC-labeled mature human DCs were also shown to migrate from a NOD/SCID mouse thigh subcutaneous injection site to the draining popliteal lymph node within 18 h of injection [ 39 ]; immature DCs, on the contrary, did not leave the injection site. Ku and coworkers used an in situ cell labeling approach, where PFC nanoemulsion was injected intradermally and taken up by resident DCs, in an effort to visualize DCs migrating into GL261 CNS glioma tumors [ 59 ] (Table 1 ). Injection of rhodamine-conjugated PFC nanoemulsion in either wild type or Erk −/− C57BL/6 mice showed greater fluorine labeled DCs migrating into tumor tissue of Erk −/− C57BL/6 mice and as a result, slower tumor growth.…”

Performance of compressed sensing for fluorine‐19 magnetic resonance imaging at low signal‐to‐noise ratio conditions

“…CS will be particularly useful in studies that involve small amounts of 19 F, as is the case in pharmacokinetic studies 47 as well as studies involving 19 F-target-specific theranostic nanoparticles, 48 19 F/ 1 H MR smart probes, 49,50 or 19 F-labeled cells administered as therapies for tumor disease. 2,51…”

Genetically modified cancer vaccines: Current status and future prospects

“…Immunosuppressive factors expressed in DCs may contribute to this process; thus, silencing these genes could amplify the immune responses and antitumor ability of DC vaccines, and viruses are the most widely used vectors during this progress 75,76 . For example, in a murine glioma model, researchers found that signal‐regulated kinase (ERK1)‐deficient DCs appeared to show increased migration and provide survival benefits, which were proven to be associated with the increased expression of actin‐associated cytoskeletal organizing proteins and sustained Cdc42 activation 77 . So the combination of the inhibition of immune checkpoint molecules with the overexpression of TAAs or other immune activators has been tested in recent years.…”