美国罗切斯特大学Minsoo Kim团队近期取得重要工作进展，他们研究发现ST3GAL1和βII-spectrin通路控制CAR T细胞向靶向肿瘤的迁移。相关研究成果2023年4月17日在线发表于《自然—免疫学》杂志上。

据介绍，过继转移基因工程嵌合抗原受体（CAR）T细胞正成为血液系统恶性肿瘤的一种有前途的治疗选择。然而，T细胞免疫疗法在实体瘤患者中大多失败了。

研究人员利用CRISPR–Cas9混合文库进行了体内靶向功能丢失筛查，并确定ST3β-半乳糖苷α-2,3-唾液酸转移酶1（ST3GAL1）是CAR T细胞癌特异性迁移的负调控因子。糖基化蛋白的分析显示，CD18是ST3GAL1在活化的CD8⁺ T细胞中的主要效应物。ST3GAL1介导的糖基化通过改变淋巴细胞功能相关抗原-1（LFA-1）的内吞循环诱导T细胞的自发非特异性组织隔离。βII-spectrin是一种中心LFA-1-相关的细胞骨架分子，其表达增强的工程CAR T细胞通过改善CAR T细胞的肿瘤特异性归巢，逆转了ST3GAL1介导的非特异性T细胞迁移，并减少了小鼠的肿瘤生长。

总之，这些发现确定了ST3GAL1–βII-spectrin轴是癌症靶向CAR T细胞迁移的主要细胞固有程序，也是一种有前途的有效T细胞免疫治疗策略。

附：英文原文

Title: ST3GAL1 and βII-spectrin pathways control CAR T cell migration to target tumors

Author: Hong, Yeonsun, Walling, Brandon L., Kim, Hye-Ran, Serratelli, William S., Lozada, John R., Sailer, Cooper J., Amitrano, Andrea M., Lim, Kihong, Mongre, Raj Kumar, Kim, Kyun-Do, Capece, Tara, Lomakina, Elena B., Reilly, Nicholas S., Vo, Kevin, Gerber, Scott A., Fan, Tan-Chi, Yu, Alice Lin-Tsing, Oakes, Patrick W., Waugh, Richard E., Jun, Chang-Duk, Reagan, Patrick M., Kim, Minsoo

Issue&Volume: 2023-04-17

Abstract: Adoptive transfer of genetically engineered chimeric antigen receptor (CAR) T cells is becoming a promising treatment option for hematological malignancies. However, T cell immunotherapies have mostly failed in individuals with solid tumors. Here, with a CRISPR–Cas9 pooled library, we performed an in vivo targeted loss-of-function screen and identified ST3 β-galactoside α-2,3-sialyltransferase 1 (ST3GAL1) as a negative regulator of the cancer-specific migration of CAR T cells. Analysis of glycosylated proteins revealed that CD18 is a major effector of ST3GAL1 in activated CD8+ T cells. ST3GAL1-mediated glycosylation induces the spontaneous nonspecific tissue sequestration of T cells by altering lymphocyte function-associated antigen-1 (LFA-1) endocytic recycling. Engineered CAR T cells with enhanced expression of βII-spectrin, a central LFA-1-associated cytoskeleton molecule, reversed ST3GAL1-mediated nonspecific T cell migration and reduced tumor growth in mice by improving tumor-specific homing of CAR T cells. These findings identify the ST3GAL1–βII-spectrin axis as a major cell-intrinsic program for cancer-targeting CAR T cell migration and as a promising strategy for effective T cell immunotherapy.

DOI: 10.1038/s41590-023-01498-x

Source: https://www.nature.com/articles/s41590-023-01498-x