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CXCL10-induced intratumoral chemotaxis of ex vivo-expanded natural killer cells in combination with NKTR-255 significantly reduces tumor burden and increases survival in an osteosarcoma xenograft model

ABSTRACT: Recurrent 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. Ex vivo expansion of NK cells significantly increases the expression of CXCR3, one of the major proteins in the regulation of NK cell chemotaxis. We hypothesize that inducing OSA cells to secrete ligands to CXCR3, CXCL9, -10 or -11 enhances expanded NK cell chemotaxis to the OSA TME, leading to reduced OSA xenograft tumor burden and increased animal survival following treatment with expanded NK cells alone or in combination with an interleukin (IL)-15 agonist, NKTR-255. OSA cells were engineered to secrete CXCL9, -10 or -11 by viral transduction. The in vitro NK migration toward conditioned media was investigated by transwell assay. The xenograft mouse OSA model was utilized to assess NK migration/infiltration, tumor progression and animal survival following treatment with expanded NK cells alone or in combination with NKTR-255. Single cell RNA sequencing (scRNA-seq) and mass cytometry were utilized to identify the response/resistance mechanisms to the combinatorial therapy of NK cells and NKTR-255. Engineered over-secretion of CXCL9, -10 or -11, from OSA cells significantly enhanced expanded NK cell migration towards 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=0.04), and concomitant treatment with NKTR-255 further reduced (p=0.02) tumor burden and significantly increased survival in mice bearing CXCL10-secreting tumors compared with those with wild-type tumors (p=0.02). ScRNA-seq and mass cytometry revealed upregulated apoptosis and TGF-β signaling as the potential mechanisms of response/resistance to NK cell therapy in vivo. Our findings highlight the potential application of chemokine-enhanced NK tumor infiltration in combination with an IL--15 agonist as a novel approach in the effective treatment of poor-risk OSA. Concomitant use of immune checkpoint inhibitors and/or anti-TGF-β therapy needs to be explored to overcome the resistance mechanisms to this novel therapy.

ORGANISM(S): Homo sapiens/Mus musculus xenograft

PROVIDER: GSE297427 | GEO | 2025/06/10

REPOSITORIES: GEO

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CXCL10-induced intratumoral chemotaxis of ex vivo-expanded natural killer cells in combination with NKTR-255 significantly reduces tumor burden and increases survival in an osteosarcoma xenograft model

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