Modulation Of Glioblastoma Immune Microenvironment Through Immune Cell-mediated Delivery Of Nanodiamond-polyglycerol-doxorubicin Composites

Glioblastoma(GBM)is the deadliest and most common type of malignant primary brain tumor in adults with a poor prognosis and high mortality.Chemotherapy is the major way for GBM.Blood brain barrier(BBB)restricts the access of most drugs to the GBM tissue.Therefore,drug delivery to GBM is an important problem in the therapy of GBM.More importantly,the immunosuppressed microenvironment can promote the survival,progression and induce therapy resistance of GBM along with suppressing the immune system of human.Hence,remodeling the immune microenvironment of GBM is the most important strategy.On the other hand,large numbers of circulated inflammatory cells can be recruited by GBM.In the microenvironment of GBM,infiltration of a large number of immunosuppressed immune cells(Tumor assoiated macrophage(TAM)and dendritic cell(DC))and lack of effective lymphocytes are the most important factors of GBM deterioration.Consequently,delivering drugs and regulating the immune microenvironment of GBM with GBM regulated immune cells are important anti-GBM novel strategies.In the previous work,we designed nanodimond-polyglycerol-doxorubicin composites(Nano-DOX)and delivered Nano-DOX with monocyte.Nano-DOX stimulated increased damage associated molecular patterns(DAMPs),which can induce immunogenic cell death(ICD)and active immunocytes,released from GBM.Based on this,we speculated that TAM and DC in GBM could be used as tools to deliver Nano-DOX to GBM and further modulate its immune microenvironment.Our research demonstrates the above hypothesis through in vivo and in vitro studies.Our results showed the following important findings.1)TAM and DC could tolerate and load Nano-DOX compared with free doxorubicin(DOX).2)In the research,TAM and DC can be used as carriers to deliver Nano-DOX to GBM cell(GC),damage GC and induce ICD effect.3)Nano-DOX can not only reprogram immunosuppressive TAM into immunostimulative type-I macrophage,4)but also active DC-driven lymphocyte-mediated anti-GBM immune response through impacting GC.5)In addition,our results also confirmed that Nano-DOX can stimulate immunogenicity of GC through inducing cell autophagy,which consist of stimulating antigens and DAMPs released from GC.In conclusion,this research demonstrated TAM and DC can be used to deliverNano-DOX to GBM and further modulate the immune microenvironment of GBM.Meanwhile,our findings also suggest that activation of autophagy is a central mechanism whereby Nano-DOX stimulates GC's immunogenicity and mediates activation of immunocytes.By this work,we present a novel approach with great application potential to subvert immune microenvironment of GBM and to anti-GBM immunotherapy.