Hefei national Research Center for Physical Sciences at the Microscale, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.
Nat Commun. 2024 Feb 9;15(1):1213. doi: 10.1038/s41467-024-45208-z.
Dysfunction of invariant natural killer T (iNKT) cells contributes to immune resistance of tumors. Most mechanistic studies focus on their static functional status before or after activation, not considering motility as an important characteristic for antigen scanning and thus anti-tumor capability. Here we show via intravital imaging, that impaired motility of iNKT cells and their exclusion from tumors both contribute to the diminished anti-tumor iNKT cell response. Mechanistically, CD1d, expressed on macrophages, interferes with tumor infiltration of iNKT cells and iNKT-DC interactions but does not influence their intratumoral motility. VCAM1, expressed by cancer cells, restricts iNKT cell motility and inhibits their antigen scanning and activation by DCs via reducing CDC42 expression. Blocking VCAM1-CD49d signaling improves motility and activation of intratumoral iNKT cells, and consequently augments their anti-tumor function. Interference with macrophage-iNKT cell interactions further enhances the anti-tumor capability of iNKT cells. Thus, our findings provide a direction to enhance the efficacy of iNKT cell-based immunotherapy via motility regulation.
固有自然杀伤 T(iNKT)细胞功能障碍导致肿瘤的免疫抵抗。大多数机制研究集中在它们在激活前后的静态功能状态上，而不考虑运动性作为抗原扫描的一个重要特征，从而影响其抗肿瘤能力。在这里，我们通过活体成像显示，iNKT 细胞运动能力受损及其从肿瘤中的排除，均导致抗肿瘤 iNKT 细胞反应减弱。在机制上，巨噬细胞上表达的 CD1d 干扰 iNKT 细胞浸润肿瘤和 iNKT-DC 相互作用，但不影响其肿瘤内运动性。癌细胞表达的 VCAM1 通过降低 CDC42 表达来限制 iNKT 细胞的运动性，并抑制其与 DC 的抗原扫描和激活。阻断 VCAM1-CD49d 信号可改善肿瘤内 iNKT 细胞的运动性和激活，从而增强其抗肿瘤功能。干扰巨噬细胞-iNKT 细胞相互作用进一步增强了 iNKT 细胞的抗肿瘤能力。因此，我们的发现为通过调节运动性来增强 iNKT 细胞为基础的免疫疗法的疗效提供了一个方向。
