Antitumor Immunotherapy Delivery System Based On MDSC Recruitment And Recruitment Inhibition

Myeloid-derived suppressor cells(MDSCs)were constituted by a diverse population of myeloid progenitor and precursor cells at various stages of differentiation that exert a crucial role in the suppression of antitumor immune responses.Cancer patients with high populations of MDSCs have almost twice the likelihood of death,and circulating MDSCs can serve as a predictive marker for advanced-stage and poor prognosis in cancer patients,conferring resistance of patients to immune checkpoint inhibitors(CPIs).In essence,MDSCs represent the principal immunosuppressive cells within the tumor microenvironment(TME)and serve as a fundamental component of the protective shield that shields tumors from both the patient’s immune system and immunotherapeutic interventions.Breaking immunosuppressive TME requires targeting MDSCs to eliminate MDSC immunosuppressive cytokines and activate the patient’s immune system to attack the tumor.In this paper,we present the principal findings and academic contributions of our research:1)A mechanism underlying the MDSCs-associated recurrence of glioblastoma(GBM)after chemoradiotherapy was unraveled.Our findings reveal that chemoradiotherapy activates endothelial inflammatory signaling around GBM and selectively upregulates the expression of vascular cell adhesion molecule-1(VCAM-1)and intercellular adhesion molecule-1(ICAM-1).It appears that the immunosuppression-related MDSCs,particularly monocytic MDSCs(M-MDSCs),exhibit a greater propensity to be recruited by these adhesion factors.These M-MDSCs utilize VCAM-1and ICAM-1 on the endothelial cell surface to infiltrate the TME and subsequently overexpress programmed death-ligand 1(PD-L1),which effectively hinders the function of cytotoxic T cells and thereby,facilitates GBM evasion of immune system surveillance and promotes its relapse.2)A strategy for drug delivery using M-MDSC recruitment to cross the blood-brain barrier(BBB)was proposed.Our research has shown that radiotherapy or chemotherapy can promote the activation of endothelial inflammatory signaling around tumors,upregulate VCAM-1 and ICAM-1 expression,and aid GBM cells in mobilizing M-MDSCs throughout the entire organism and utilizing these cells to express PD-L1 to evade immune system detection.In light of these findings,we propose a novel drug delivery system termedαLy-6C-LAMP,which can effectively target M-MDSCs with long-lasting effects in the periphery,cause peripheral M-MDSCs to engulf the PD-L1 trap plasmid and carry the PD-L1 trap plasmid across the BBB into the TME,where they can express the PD-L1 trap protein under the influence of the plasmid for blocking the intra-tumoral PD-1/PD-L1 pathway.αLy-6C-LAMP showed good anti-PD-L1 efficacy in vitro,blocking both self and pericyte surface PD-L1 protein molecules.A single intravenous injection ofαLy-6C-LAMP can maintain high levels of PD-L1 trap protein in GBM tumors for 3-5 days,and two doses ofαLy-6C-LAMP during the treatment period significantly inhibit the recurrence of GBM-bearing mice following conventional treatment.3)An antitumor adjuvant therapy that inhibits the recruitment of MDSCs was developed.Indoleamine 2,3-dioxygenase 1(IDO1)is required for the recruitment of MDSCs to tumors,and inhibition of IDO1 has been shown to suppress the expansion of CD11b~+cells in tumors.Breast cancer(BC)is one of the most common cancers,and IDO1 expression has been associated with its disease progression.To evaluate the effect of local IDO1 inhibition on MDSC recruitment,we developed a BC-bearing mouse model using 4T1 cells and prepared a novel nanocarrier,MP/A-IND,for delivering the IDO1inhibitor indoximod(IND).The number of intratumoral M-MDSCs decreased to 6%,and polymorphonuclear MDSCs(PMN-MDSCs)decreased to 51%in BC-bearing mice treated with MP/A-IND treatment.In addition to targeting the tumor,a portion of MP/A-IND is taken up by intratumoral dendritic cells(DCs)and enters the tumor-draining lymph node(TDLN)to participate in antigen presentation.Ultimately MP/A-IND enhanced the antitumor immune response and inhibited tumor growth.Our study has established a correlation between GBM recurrence after chemoradiotherapy and the recruitment of M-MDSCs,and developed a drug delivery system namedαLy-6C-LAMP that can effectively target M-MDSCs in the peripheral region with sustained therapeutic effects,which successfully blocked the intra-tumoral PD-1/PD-L1 pathway in tumors by utilizing a mediated drug delivery strategy.Additionally,we have prepared a novel nanocarrier MP/A-IND to investigate the role of inhibiting the recruitment of intratumoral MDSCs in the antitumor immune response.Collectively,our findings provide a comprehensive perspective on the advantages of modulating MDSCs against the antitumor immune response,which offers new ideas and approaches to overcome the tumor immunosuppressive barrier and enhance antitumor immune efficacy.