As a key component of the standard of care for glioblastoma, radiotherapy induces several immune resistance mechanisms, such as upregulation of CD47 and PD-L1. Here, leveraging these radiotherapy-elicited processes, we generate a bridging-lipid nanoparticle (B-LNP) that engages tumor-associated myeloid cells (TAMCs) to glioblastoma cells via anti-CD47/PD-L1 dual ligation. We show that the engager B-LNPs block CD47 and PD-L1 and promote TAMC phagocytic activity. To enhance subsequent T cell recruitment and antitumor responses after tumor engulfment, the B-LNP was encapsulated with diABZI, a non-nucleotidyl agonist for stimulator of interferon genes. In vivo treatment with diABZI-loaded B-LNPs induced a transcriptomic and metabolic switch in TAMCs, turning these immunosuppressive cells into antitumor effectors, which induced T cell infiltration and activation in brain tumors. In preclinical murine models, B-LNP/diABZI administration synergized with radiotherapy to promote brain tumor regression and induce immunological memory against glioma. In summary, our study describes a nanotechnology-based approach that hijacks irradiation-triggered immune checkpoint molecules to boost potent and long-lasting antitumor immunity against glioblastoma.
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.
IntroductionThe immunosuppressive tumor microenvironment (TME) is a major barrier to the efficacy of chimeric antigen receptor T cells (CAR-T cells) in glioblastoma (GBM). Transgenic expression of IL15 is one attractive strategy to modulate the TME. However, at present, it is unclear if IL15 could be used to directly target myeloid-derived suppressor cells (MDSCs), a major cellular component of the GBM TME. Here, we explored if MDSC express IL15Rα and the feasibility of exploiting its expression as an immunotherapeutic target.MethodsRNA-seq, RT-qPCR, and flow cytometry were used to determine IL15Rα expression in paired peripheral and tumor-infiltrating immune cells of GBM patients and two syngeneic murine GBM models. We generated murine T cells expressing IL13Rα2-CARs and secretory IL15 (CAR.IL15s) or IL13Rα2-CARs in which IL15 was fused to the CAR to serve as an IL15Rα-targeting moiety (CAR.IL15f), and characterized their effector function in vitro and in syngeneic IL13Rα2+glioma models.ResultsIL15Rα was preferentially expressed in myeloid, B, and dendritic cells in patients’ and syngeneic GBMs. In vitro, CAR.IL15s and CAR.IL15f T cells depleted MDSC and decreased their secretion of immunosuppressive molecules with CAR.IL15f T cells being more efficacious. Similarly, CAR.IL15f T cells significantly improved the survival of mice in two GBM models. TME analysis showed that treatment with CAR.IL15f T cells resulted in higher frequencies of CD8+T cells, NK, and B cells, but a decrease in CD11b+cells in tumors compared with therapy with CAR T cells.ConclusionsWe demonstrate that MDSC of the glioma TME express IL15Ra and that these cells can be targeted with secretory IL15 or an IL15Rα-targeting moiety incorporated into the CAR. Thus, IL15-modified CAR T cells act as a dual targeting agent against tumor cells and MDSC in GBM, warranting their future evaluation in early-phase clinical studies.
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