期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2107507118
关键词
natural killer cells; glioblastoma; autophagy; CD73; immunotherapy
资金
- V Foundation for Cancer Research [D2019-039]
- Walther Cancer Foundation [0186.01]
- Collaborative Core for Cancer Bioinformatics
- Biological Evaluation Shared Resource
- Flow Cytometry Shared Resource
- Purdue Center for Cancer Research
- NIH [P30 CA023168]
- Indiana University Simon Cancer Center NIH [P30 CA082709]
This study demonstrates a promising strategy utilizing genetically engineered human NK cells as a multifunctional immunotherapy to target multiple mechanisms of GBM progression simultaneously, including addressing antigen escape, immunometabolic reprogramming, and immune cell homing.
Tumor antigen heterogeneity, a severely immunosuppressive tumor microenvironment (TME) and lymphopenia resulting in inadequate immune intratumoral trafficking, have rendered glioblastoma (GBM) highly resistant to therapy. To address these obstacles, here we describe a unique, sophisticated combinatorial platform for GBM: a cooperative multifunctional immunotherapy based on genetically engineered human natural killer (NK) cells bearing multiple antitumor functions including local tumor responsiveness that addresses key drivers of GBM resistance to therapy: antigen escape, immunometabolic reprogramming of immune responses, and poor immune cell homing. We engineered dualspecific chimeric antigen receptor (CAR) NK cells to bear a third functional moiety that is activated in the GBM TME and addresses immunometabolic suppression of NK cell function: a tumorspecific, locally released antibody fragment which can inhibit the activity of CD73 independently of CAR signaling and decrease the local concentration of adenosine. The multifunctional human NK cells targeted patient-derived GBM xenografts, demonstrated local tumor site-specific activity in the tissue, and potently suppressed adenosine production. We also unveil a complex reorganization of the immunological profile of GBM induced by inhibiting autophagy. Pharmacologic impairment of the autophagic process not only sensitized GBM to antigenic targeting by NK cells but promoted a chemotactic profile favorable to NK infiltration. Taken together, our study demonstrates a promising NK cell-based combinatorial strategy that can target multiple clinically recognized mechanisms of GBM progression simultaneously.
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