St3gal1 and bII-spectrin pathways control CAR-T cell migration to target tumor sites [3]
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ABSTRACT:
PROVIDER: PRJNA945418 | ENA |
REPOSITORIES: ENA
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Project description:Adoptive transfer of genetically engineered chimeric antigen receptor (CAR)-T cell is emerging as a promising treatment option for hematological malignancies. However, T cell immunotherapies have largely failed in patients with solid tumors. Here, with a CRISPR-Cas9 pooled library, we performed an in vivo targeted loss-of-function screen and identified ST3 b-galactoside a-2,3-sialyltransferase 1 (St3gal1) as a key negative regulator of the cancer-specific migration of CAR-T cells. Analysis of glycosylated proteins reveals 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 bII-spectrin, a key LFA-1 associated cytoskeleton molecule, reversed St3gal1-mediated nonspecific T cell migration and significantly reduced tumor growth in mice by improving tumor-specific homing of CAR-T cells. These findings identify a role of the St3gal1- bII-spectrin axis as the key cell-intrinsic program for cancer targeting CAR-T cell migration and as a promising strategy for effective T cell immunotherapy.
2023-03-17 | GSE227509 | GEO
Project description:Adoptive transfer of genetically engineered chimeric antigen receptor (CAR)-T cell is emerging as a promising treatment option for hematological malignancies. However, T cell immunotherapies have largely failed in patients with solid tumors. Here, with a CRISPR-Cas9 pooled library, we performed an in vivo targeted loss-of-function screen and identified ST3 b-galactoside a-2,3-sialyltransferase 1 (St3gal1) as a key negative regulator of the cancer-specific migration of CAR-T cells. Analysis of glycosylated proteins reveals 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 bII-spectrin, a key LFA-1 associated cytoskeleton molecule, reversed St3gal1-mediated nonspecific T cell migration and significantly reduced tumor growth in mice by improving tumor-specific homing of CAR-T cells. These findings identify a role of the St3gal1- bII-spectrin axis as the key cell-intrinsic program for cancer targeting CAR-T cell migration and as a promising strategy for effective T cell immunotherapy.
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Project description:Adoptive transfer of genetically engineered chimeric antigen receptor (CAR)-T cell is emerging as a promising treatment option for hematological malignancies. However, T cell immunotherapies have largely failed in patients with solid tumors. Here, with a CRISPR-Cas9 pooled library, we performed an in vivo targeted loss-of-function screen and identified ST3 b-galactoside a-2,3-sialyltransferase 1 (St3gal1) as a key negative regulator of the cancer-specific migration of CAR-T cells. Analysis of glycosylated proteins reveals 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 bII-spectrin, a key LFA-1 associated cytoskeleton molecule, reversed St3gal1-mediated nonspecific T cell migration and significantly reduced tumor growth in mice by improving tumor-specific homing of CAR-T cells. These findings identify a role of the St3gal1- bII-spectrin axis as the key cell-intrinsic program for cancer targeting CAR-T cell migration and as a promising strategy for effective T cell immunotherapy.
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Project description:St3gal1 and bII-spectrin pathways control CAR-T cell migration to target tumor sites
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Project description:St3gal1 and bII-spectrin pathways control CAR-T cell migration to target tumor sites [2]
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Project description:St3gal1 and bII-spectrin pathways control CAR-T cell migration to target tumor sites [1]
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Project description:Immunotherapies with CAR-T cells achieve remarkable success, especially against B-cell malignancies. However, their activity against non-hematopoietic solid tumors is very limited. One central cause of this failure may be that a pro-oxidative tumor microenvironment can downmodulate the activation and migration of T-cells. In contrast to tumor cells, primary T cells have very low levels of antioxidants. This makes them prone to pro-oxidative effects. Oxidation-induced dysregulation of actin cytoskeletal dynamics hinders T-cell migration which allows only low tumor infiltration rates. In addition, the proliferation and the effector functions of T-cells (tumor cell killing) are disrupted. In order to strengthen human CAR-T cells against a pro-oxidative tumor microenvironment, we have increased increase their antioxidant capacity, e.g. by expressing antioxidants. We aimed to characterize the importance of antioxidant empowerment at functional level and at the molecular level. Among the antioxidant systems, thioredoxin1 (TRX1)-empowerment, allowed CAR T cells to retain their capacities for cytolytic immune synapse formation, cytokine release, proliferation, and cytotoxicity under pro-oxidative conditions. At the molecular level, gene expression analysis revealed that a pro-oxidative micromilieu caused a downmodulation of costimulatory and cytokine signals of T cells. One unique focus of this study was also to investigate global influence of reactive oxygen species on protein oxidation in T cells. Therefore, using TRX1 kinetic trapping and consequently mass spectrometry was employed to get insight into global oxidation levels in T cells. This analysis, namely redoxosome analysis, unveiled 196 oxidized proteins which were annotated to regulate several antitumor T cell functions. Taken together, our results provide evidence that TRX1 empowerment can increase CAR T cell efficacy against solid tumors.
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