Yoon Jong Hyeon, Yoon Han-Na, Kang Hyun Ju, Yoo Hyejin, Choi Moon Jung, Chung Joo-Yoon, Seo Minkoo, Kim Minsung, Lim Si On, Kim Yong Jun, Lee Jin-Ku, Jang Mihue
Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
Rare & Pediatric Cancer Branch, Division of Rare and Refractory Cancer, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea.
Mol Ther Oncol. 2024 Feb 19;32(1):200777. doi: 10.1016/j.omton.2024.200777. eCollection 2024 Mar 21.
Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells are a promising immunotherapy for solid cancers; however, their effectiveness against pancreatic cancer is limited by the immunosuppressive tumor microenvironment. In particular, low NK cell infiltration poses a major obstacle that reduces cytotoxicity. The current study aimed to enhance the tumor-homing capacity of CAR-NK cells by targeting the chemokine-chemokine receptor axis between NK and pancreatic cancer cells. To this end, data from a chemokine array and The Cancer Genome Atlas pan-cancer cohort were analyzed. Pancreatic cancer cells were found to secrete high levels of ligands for C-X-C motif receptor 1 (CXCR1) and CXCR2. Subsequently, we generated anti-mesothelin CAR-NK cells incorporating CXCR1 or CXCR2 and evaluated their tumor-killing abilities in 2D cancer cell co-culture and 3D tumor-mimetic organoid models. CAR-NK cells engineered with CXCR2 demonstrated enhanced tumor killing and strong infiltration of tumor sites. Collectively, these findings highlight the potential of CXCR2-augmented CAR-NK cells as a clinically relevant modality for effective pancreatic cancer treatment. By improving their infiltration and tumor-killing capabilities, these CXCR2-augmented CAR-NK cells have the potential to overcome the challenges posed by the immunosuppressive tumor microenvironment, providing improved therapeutic outcomes.
嵌合抗原受体（CAR）工程化自然杀伤（NK）细胞是一种有前途的实体癌免疫疗法；然而，它们对胰腺癌的有效性受到免疫抑制性肿瘤微环境的限制。特别是，NK细胞低浸润构成了降低细胞毒性的主要障碍。当前研究旨在通过靶向NK细胞与胰腺癌细胞之间的趋化因子-趋化因子受体轴来增强CAR-NK细胞的肿瘤归巢能力。为此，分析了趋化因子阵列数据和癌症基因组图谱泛癌队列数据。发现胰腺癌细胞分泌高水平的C-X-C基序受体1（CXCR1）和CXCR2的配体。随后，我们生成了整合CXCR1或CXCR2的抗间皮素CAR-NK细胞，并在二维癌细胞共培养和三维肿瘤模拟类器官模型中评估了它们的肿瘤杀伤能力。用CXCR2工程改造的CAR-NK细胞表现出增强的肿瘤杀伤能力和对肿瘤部位的强烈浸润。总体而言，这些发现突出了CXCR2增强的CAR-NK细胞作为有效治疗胰腺癌的临床相关方式的潜力。通过提高它们的浸润和肿瘤杀伤能力，这些CXCR2增强的CAR-NK细胞有潜力克服免疫抑制性肿瘤微环境带来的挑战，提供更好的治疗效果。
