| First Author | Hong Y | Year | 2023 |
| Journal | Nat Immunol | Volume | 24 |
| Issue | 6 | Pages | 1007-1019 |
| PubMed ID | 37069398 | Mgi Jnum | J:337723 |
| Mgi Id | MGI:7495987 | Doi | 10.1038/s41590-023-01498-x |
| Citation | Hong Y, et al. (2023) ST3GAL1 and betaII-spectrin pathways control CAR T cell migration to target tumors. Nat Immunol 24(6):1007-1019 |
| abstractText | 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 beta-galactoside alpha-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 betaII-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-betaII-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. |
