Abstract B36: Nano-engineering of immunosuppressive myeloid cells for immunostimulation in glioblastoma

Abstract

Abstract As a hallmark of glioblastoma (GBM), the myeloid-rich tumor microenvironment is one of the major causes of GBM immunosuppression and therapy resistance. Therefore, tumor-associated myeloid cells (TAMCs) have been identified as a promising therapeutic target for remodeling the immunologically “cold” brain tumors and overcoming the therapy resistance of GBM. Emerging research findings have uncovered the interplay between TAMCs and radiotherapy, a key component of the standard of care for GBM. While radiotherapy is known to induce antitumor immune response, in which the functionality of the myeloid compartment, including phagocytosis of tumor and subsequent activation of effector T cells, plays a key role, irradiation also triggers immune resistance mechanisms, such as the overexpression of anti-phagocytic molecule CD47 in gliomas and immune checkpoint molecule PD-L1 in TAMCs. To tackle this, a bispecific-lipid nanoparticle (B-LNP) was designed to hijack the irradiation-induced upregulation of immunosuppressive molecules for harnessing TAMCs to elicit antitumor immune response. The B-LNP was surface functionalized with anti-CD47/PD-L1 ligands to enable a simultaneous targeting of TAMCs and glioma cells through dual ligation. The engineered B-LNP effectively bound to and blocked CD47 and PD-L1 molecules, and served as a bridge to engage TAMCs for enhanced phagocytosis of glioma cells when combined with radiotherapy. To promote the TAMC-mediated activation of adaptive antitumor immunity post-phagocytosis, diABZI, a synthetic non-nucleotidyl agonist for stimulator of interferon genes (STING), was physically encapsulated into B-LNP as a payload therapeutic. Our results indicate that B-LNP/diABZI complex enabled a TAMC-specific STING activation in preclinical murine glioma model CT-2A, which transformed the immunosuppressive TAMCs into tumor-eradicating cells in the glioma microenvironment, as evidenced by immune profiling, single-cell RNA sequencing analysis, and bulk metabolomics. As a result, the nano-engineered TAMCs dramatically promoted tumor infiltration and anti-glioma activity of T cells, which improved the therapeutic outcome of radiotherapy, eradicating tumors from about 70% of the glioma-bearing mice, and generated a long-lasting immunological memory against gliomas. The translational potential of our nano-engineering approach was further validated using a glioma model that recapitulates the genetic, histological, and immunological features of human GBM, and using the clinical tumor specimens of GBM patients. In conclusion, our work demonstrates a nanotechnology-mediated immunomodulatory approach that targets and modulates the myeloid-rich GBM microenvironment as a combinatorial treatment for improving the existing standard of care for GBM. Citation Format: Peng Zhang, Aida Rashidi, Junfei Zhao, Brandyn Castro, Abby Ellingwood, Yu Han, Aurora Lopez-Rosas, Markella Zannikou, Crismita Dmello, Rebecca Levine, Ting Xiao, Alex Cordero, Adam M Sonabend, Irina V Balyasnikova, Catalina Lee-Chang, Jason Miska, Maciej S Lesniak. Nano-engineering of immunosuppressive myeloid cells for immunostimulation in glioblastoma [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B36.