Wang, JiaoToregrosa-Allen, SandraElzey, Bennett D.Utturkar, SagarLanman, Nadia AtallahBernal-Crespo, VictorBehymer, Matthew M.Knipp, Gregory T.Yun, YeonheeVeronesi, Michael C.Sinn, Anthony L.Pollok, Karen E.Brutkiewicz, Randy R.Nevel, Kathryn S.Matosevic, Sandro2023-06-152023-06-152021Wang J, Toregrosa-Allen S, Elzey BD, et al. Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells. Proc Natl Acad Sci U S A. 2021;118(45):e2107507118. doi:10.1073/pnas.2107507118https://hdl.handle.net/1805/33788Tumor 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 dual-specific 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 tumor-specific, 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.en-USPublisher PolicyNatural killer cellsGlioblastomaAutophagyImmunotherapyArticle