CD56brightcytokine-induced memory-like NK cells and NK-cell engagers synergize against non-small cell lung cancer cancer-stem cells

• DOI: 10.1136/jitc-2024-010205
• Publication Date: 2025-02-12T18:20:24Z
• Authors: Maria L Guevara L...; Ann Gebo; Monica Parodi; Stefano Persano; Josephine Maus-Conn; Maria Cristina Mi...; Fabrizio Loiacono; Paola Orecchia; Simona Sivori; Claudia Cantoni; Marco Gentili; Federica Facchinetti; Riccardo Ferracini; Daniel A Vallera; Martin Felices; Giulia Bertolini; Marco Pravetoni; Luca Roz; Massimo Vitale
• Keywords: Lymphokine-activated killer cell; NK-92; TIGIT

Background Due to their enhanced responsiveness and persistence, cytokine-induced memory-like (CIML)-natural killer (NK) cells have emerged as new immunotherapeutic tools against malignancies. However, effects on tumor-cell spread metastases in solid tumors remain poorly investigated. Moreover, a clear identification of the most effective CIML-NK subsets, especially controlling cancer stem (CSC), is still lacking. Methods We performed combined phenotypical functional analyses cell either selected by flow-cytometry gating, or generated from sorted CD56 bright /CD56 dim NK cells. By co-culture experiments, we analyzed effect non-small lung (NSCLC) spheroids, patient-derived xenografts (PDX), assessing changes CSC content, tumorigenicity, and/or tumor disseminating capability vivo. were also infused PDX-bearing mice validate dissemination PDX lungs. Finally, functionally patients with stages I/III NSCLC (n=6). Results show that exert antitumor activity mostly through subset, which greatly expands during CIML differentiation. Compared conventionally activated interleukin-2, express lower levels check-point receptors, TIGIT TIM3, higher effector functions PDX, vitro-generated spheroids. Remarkably, significantly reduce CSC-containing CD133 + subpopulation within spheroids limit tumorigenicity ability disseminate CSCs primary distant sites. Sorting experiments subsets reveal drive this anti-CSC activity, suggest such advantage could be related increased expression LFA-1 ICAM-1 CSCs, respectively. tri-specific engager (TriKE) 1615133 enhances CSCs. demonstrate cells, capable killing autologous responding TriKE, induced NSCLC. Conclusions Our study discloses for first time therapeutic potential metastatic spread, highlighting role subset expansion TriKE optimizing CIML-NK-based therapies tumors.