Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells
Menée in vitro et à l'aide d'une xénogreffe de glioblastome sur un modèle murin, cette étude met en évidence l'intérêt thérapeutique de cellules NK modifiées par ingénierie pour cibler simultanément des mécanismes impliqués dans l'immunorésistance
Glioblastoma (GBM) is the most aggressive brain cancer and highly resistant to therapy, including immunotherapies. It is able to escape immune recognition due to its high heterogeneity, active immunometabolic suppression, and antigen escape mechanisms. Here, we describe an immunotherapy centered around human natural killer (NK) cells engineered to simultaneously target these pathways of immune resistance. These engineered NK cells are able to block adenosine signaling in GBM via CD73 while avoiding antigen escape. We also uncover the functional cooperation between these cells’ intratumoral infiltration and impaired autophagy in GBM as a powerful approach to traffick NK cells into the GBM niche. This NK cell–based immunotherapy provides opportunities to broaden the breadth and versatility of current therapeutic regimens for GBM.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 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.