Conflict of interest: VAA and AMS are authors of a patent filed by Northwestern University related to predicting the response to immunotherapy in gliomas (US2021071138). AMS has received in-kind and/or funding support for research from Agenus, Bristol Myers Squibb, and Carthera. RS has acted or is acting as a scientific advisor or has served on advisory boards for Alpheus Medical (formerly Craniovation), AstraZeneca, Boston Scientific, Carthera, Celularity, GT Medical, Insightech, Lockwood (BlackDiamond), Northwest Biotherapeutics, Novocure, Syneos Health (Boston Biomedical), TriAct Therapeutics, and Varian Medical Systems. ABH serves on the advisory board of Caris Life Sciences and the WCG Oncology Advisory Board; receives royalty and milestone payments from DNAtrix for the licensing of "Biomarkers and combination therapies using oncolytic virus and immunomodulation" (patent 11,065,285); and is supported by research grants from Celu larity, Codiak BioSciences, and AbbVie. She additionally has active granted patents for "miRNA for treating cancer and for use with adoptive immunotherapies" (patent 9,675,633) and "Concurrent chemotherapy and immuno therapy" (patent 9,399,662), with a patent pending for "Low intensity ultrasound combination cancer therapies" (international applications PCT/US2022/019435 and US 63/158,642).

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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.

Purpose: Paclitaxel (PTX) is one the most potent and commonly used chemotherapies for breast and pancreatic cancer. Several ongoing clinical trials are investigating means of enhancing delivery of PTX across the blood-brain barrier for glioblastomas (GBMs). Despite the widespread use of PTX for breast cancer, and the initiative to repurpose this drug for gliomas, there are no predictive biomarkers to inform which patients will likely benefit from this therapy. Experimental Design: To identify predictive biomarkers for susceptibility to PTX, we performed a genome-wide CRISPR knock-out (KO) screen using human glioma cells. The genes whose KO was most enriched in the CRISPR screen underwent further selection based on their correlation with survival in the breast cancer patient cohorts treated with PTX and not in patients treated with other chemotherapies, a finding that was validated on a second independent patient cohort using progression-free survival. Results: Combination of CRISPR screen results with outcomes from taxane-treated breast cancer patients led to the discovery of endoplasmic reticulum (ER) protein SSR3 as a putative predictive biomarker for PTX. SSR3 protein levels showed positive correlation with susceptibility to PTX in breast cancer cells, glioma cells and in multiple intracranial glioma xenografts models. Knockout of SSR3 turned the cells resistant to PTX while its overexpression sensitized the cells to PTX. Mechanistically, SSR3 confers susceptibility to PTX through regulation of phosphorylation of ER stress sensor IRE1α. Conclusion: Our hypothesis generating study showed SSR3 as a putative biomarker for susceptibility to PTX, warranting its prospective clinical validation.