Graham Lara V, Fisher Jack G, Doyle Amber D P, Sale Ben, Del Rio Luis, French Albert J E, Mayor Neema P, Turner Thomas R, Marsh Steven G E, Cragg Mark S, Forconi Francesco, Khakoo Salim I, Blunt Matthew D
School of Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom.
School of Cancer Sciences, University of Southampton, Southampton, United Kingdom.
Front Oncol. 2024 Sep 2;14:1404051. doi: 10.3389/fonc.2024.1404051. eCollection 2024.
Strategies to mobilise natural killer (NK) cells against cancer include tumour-targeting antibodies, NK cell engagers (NKCEs) and the adoptive transfer of expanded healthy donor-derived NK cells. Genetic and functional studies have revealed that expression of the activating killer immunoglobulin-like receptor KIR2DS2 is associated with enhanced function in NK cells from healthy donors and improved outcome in several different malignancies. The optimal strategy to leverage KIR2DS2+ NK cells therapeutically is however currently unclear. In this study, we therefore evaluated the response of KIR2DS2-expressing NK cells to activation against cancer with clinically relevant tumour-targeting antibodies and following expansion. We identified that KIR2DS2 NK cells from patients with chronic lymphocytic leukaemia and hepatocellular carcinoma had enhanced activation in response to tumour-targeting antibodies compared to KIR2DS2- NK cells. However, the superior function of healthy donor derived KIR2DS2 NK cells was lost following expansion which is required for adoptive transfer-based therapeutic strategies. These data provide evidence that targeting KIR2DS2 directly in cancer patients may allow for the utilisation of their enhanced effector function, however such activity may be lost following their expansion.
调动自然杀伤（NK）细胞对抗癌症的策略包括肿瘤靶向抗体、NK细胞衔接器（NKCEs）以及扩增健康供体来源的NK细胞并进行过继性转移。基因和功能研究表明，激活型杀伤免疫球蛋白样受体KIR2DS2的表达与健康供体NK细胞功能增强以及多种不同恶性肿瘤的预后改善相关。然而，目前尚不清楚利用KIR2DS2+ NK细胞进行治疗的最佳策略。因此，在本研究中，我们评估了表达KIR2DS2的NK细胞对临床相关肿瘤靶向抗体激活的反应以及扩增后的反应。我们发现，与KIR2DS2- NK细胞相比，慢性淋巴细胞白血病和肝细胞癌患者的KIR2DS2 NK细胞对肿瘤靶向抗体的激活反应增强。然而，健康供体来源的KIR2DS2 NK细胞在扩增后丧失了其优越功能，而扩增是基于过继性转移的治疗策略所必需的。这些数据表明，直接在癌症患者中靶向KIR2DS2可能允许利用其增强的效应器功能，然而这种活性在其扩增后可能会丧失。
