Transcriptomics

Dataset Information

0

Evaluating Novel Therapeutic Strategies to Enhance CAR-T Cell Efficacy Using Patient-Derived Organotypic Tumor Spheroids


ABSTRACT: Novel therapeutic strategies are needed to improve the efficacy of chimeric antigen receptor (CAR)-T cells in the treatment of solid tumors. Multiple tumor microenvironmental factors are thought to contribute to CAR-T cell therapy resistance in solid tumors, and appropriate model systems to identify and examine these factors using clinically relevant biospecimens are limited. Here, we examined the activity of B7-H3 (CD276) directed CAR-T (B7-H3.CAR-T) using 3D microfluidic cultures of patient-derived organotypic tumor spheroids (PDOTS) and confirmed activity of B7-H3.CAR-T in PDOTS. While B7-H3 expression in PDOTS was associated with B7-H3.CAR-T sensitivity, mechanistic studies revealed dynamic upregulation of co-inhibitory receptors on CAR-T cells following target cell encounter that led to CAR-T cell dysfunction and limited efficacy against B7-H3 expressing tumors. PD-1 blockade restored CAR-T activity in monotypic and organotypic tumor spheroids with improved tumor control and upregulation of effector cytokines. Given the emerging role of TANK-binding kinase 1 (TBK1) as an immune evasion gene, we examined the effect of TBK1 inhibition on CAR-T efficacy. Similar to PD-1 blockade, TBK1 inhibition restored CAR-T activity in monotypic and organotypic tumor spheroids, prevented CAR-T cell dysfunction, and enhanced T cell proliferation. Inhibition or deletion of TBK1 also enhanced sensitivity of cancer cells to immune-mediated killing. Taken together, our results demonstrate the feasibility and utility of ex vivo profiling of CAR-T cells using PDOTS and suggest that targeting TBK1 is a novel strategy to enhance CAR-T efficacy by overcoming tumor-intrinsic and -extrinsic resistance mechanisms.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277569 | GEO | 2024/09/24

REPOSITORIES: GEO

Dataset's files

Source:
Action DRS
Other
Items per page:
1 - 1 of 1

Similar Datasets

2024-04-03 | GSE247355 | GEO
| 2400863 | ecrin-mdr-crc
2024-08-22 | GSE275242 | GEO
2024-05-08 | GSE254545 | GEO
2019-08-06 | GSE135379 | GEO
| PRJNA1162826 | ENA
2022-03-18 | GSE181437 | GEO
2024-03-27 | GSE216052 | GEO
2024-03-27 | GSE216050 | GEO
2024-03-27 | GSE216713 | GEO