IL-15-secreting CAR natural killer cells directed toward the pan-cancer target CD70 eliminate both cancer cells and cancer-associated fibroblasts
BackgroundIt remains challenging to obtain positive outcomes with chimeric antigen receptor (CAR)-engineered cell therapies in solid malignancies, like colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). A major obstacle is the lack of targetable surface antigens that are not shared by healthy tissues. CD70 emerges as interesting target, due to its stringent expression pattern in healthy tissue and its apparent role in tumor progression in a considerable amount of malignancies. Moreover, CD70 is also expressed on cancer-associated fibroblasts (CAFs), another roadblock for treatment efficacy in CRC and PDAC. We explored the therapeutic potential of CD70 as target for CAR natural killer (NK) cell therapy in CRC, PDAC, focusing on tumor cells and CAFs, and lymphoma.MethodsRNA-seq data and immunohistochemical analysis of patient samples were used to explore CD70 expression in CRC and PDAC patients. In addition, CD70-targeting CAR NK cells were developed to assess cytotoxic activity against CD70+ tumor cells and CAFs, and the effect of cytokine stimulation on their efficacy was evaluated. The in vitro functionality of CD70-CAR NK cells was investigated against a panel of tumor and CAF cell lines with varying CD70 expression. Lymphoma-bearing mice were used to validate in vivo potency of CD70-CAR NK cells. Lastly, to consider patient variability, CD70-CAR NK cells were tested on patient-derived organoids containing CAFs.ResultsIn this study, we identified CD70 as a target for tumor cells and CAFs in CRC and PDAC patients. Functional evaluation of CD70-directed CAR NK cells indicated that IL-15 stimulation is essential to obtain effective elimination of CD70+ tumor cells and CAFs, and to improve tumor burden and survival of mice bearing CD70+ tumors. Mechanistically, IL-15 stimulation resulted in improved potency of CD70-CAR NK cells by upregulating CAR expression and increasing secretion of pro-inflammatory cytokines, in a mainly autocrine or intracellular manner.ConclusionsWe disclose CD70 as an attractive target both in hematological and solid tumors. IL-15 armored CAR NK cells act as potent effectors to eliminate these CD70+ cells. They can target both tumor cells and CAFs in patients with CRC and PDAC, and potentially other desmoplastic solid tumors.
Source (journal)
Journal of hematology and oncology. - -
17 :1 (2024) , p. 1-19
Article Reference
Pubmed ID
Full text (Publisher's DOI)
Full text (open access)
Research group
Project info
Unraveling of the role and the regulation of hypoxia-inducible factors in natural killer cell functioning in hypoxic and stimulating environments.
Investigating drug repurposing and next-generation immune checkpoints to cure the incurable: novel strategies to treat pancreatic cancer.
Optimization of chimeric antigen receptor (CAR) design for improved cellular immunotherapy of hematological diseases.
Rationally designed drug combination screen in more physiologically relevant in vitro organoid models: can we improve personalized therapy for pancreatic cancer?
Improved RNA-based engineering of T lymphocytes with leukemia-specific T cell receptors to redirect their effector functions: towards a clinically safe platform to evaluate efficacy and potential off-target toxicity.
Publication type
Publications with a UAntwerp address
External links
Web of Science
Creation 04.03.2024
Last edited 07.03.2024
To cite this reference