CXCL10 诱导的体外扩增 NK 细胞趋化联合 NKTR-255 增强骨肉瘤抗肿瘤疗效

Osteosarcoma (OSA) has a dismal prognosis despite surgical resection and multiagent chemotherapy. While adoptive natural killer (NK) cell therapies have been successful in hematological malignancies, the application in solid tumors is challenging due to a tumor microenvironment (TME) that impairs NK cell tumor infiltration.

Here, we found that ex vivo expansion of NK cells significantly increases the expression of C-X-C motif chemokine receptor 3 (CXCR3), one of the major proteins in the regulation of NK cell chemotaxis. Engineered over-secretion of CXCR3 ligands, C-X-C motif chemokine ligand (CXCL)9, -10, or -11, from OSA cells significantly enhanced expanded NK cell migration toward OSA cells in vitro and infiltration into the TME in vivo , with the highest NK infiltration rate in CXCL10-secreting tumors.

Infusions of expanded NK cells significantly reduced ( p = 0. 02), and concomitant treatment with an interleukin (IL)-15 agonist NKTR-255 further reduced tumor burden and significantly increased survival in mice bearing CXCL10-secreting tumors compared with those with wild-type tumors ( p = 0. 02). Single-cell RNA sequencing and mass cytometry revealed upregulated apoptosis and transforming growth factor- (TGF- ) signaling as the potential mechanisms of response/resistance to NK cell therapy in vivo .

Our findings highlight potential application of chemokine-enhanced NK tumor infiltration in combination with an IL-15 agonist as a novel approach to effective treatment of OSA.