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In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function
Published on: February 27, 2019
In vivo screening reveals cell-intrinsic mediators of solid tumor resistance to CAR T cell-therapy
Abstract:
Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of hematologic cancers. However, its efficacy in solid tumors, including pancreatic ductal adenocarcinoma (PDAC), has been limited. By integrating modular CRISPR screening with immunocompetent orthotopic models of PDAC, we identified unknown tumor-intrinsic modulators of CAR T-cell therapy response. Disruption of genes involved in oxidative and proteotoxic stress, particularly the Nrf2 target Slc33a1 , sensitizes PDAC tumors to CAR T-cell killing. Single cell gene expression analyses revealed that CAR-T resistant tumors exhibit reduced Nrf2 pathway activity. Mechanistically, we show that Nrf2 pathway hyperactivation by genetic ablation of Keap1 or expression of a tumor-derived Keap1 allele sensitized PDAC tumors to CAR T-cell therapy. Thus, cell-intrinsic molecular states accompanying malignant progression can sensitize tumor cells to cell-based immunotherapies. These molecular mechanisms could be exploited to augment both the efficacy of CAR-T cell therapy in solid malignancies, and may allow patient stratification by tumor genotype.
Statement Of Significance:
CAR T-cell therapy remains an unsolved challenge for pancreatic cancer. The discovery of tumor-intrinsic mechanisms of resistance has been largely limited by current experimental models. Using large-scale genomic screening in an orthotopic, immunocompetent model of pancreatic cancer, we uncover a role for cell-intrinsic metabolic states in regulating CAR T-cell response.
Insights
Chimeric antigen receptor (CAR) T-cell therapy shows promise for pancreatic cancer. Disrupting oxidative stress genes, like SLC33A1, sensitizes pancreatic tumors to CAR T-cells by enhancing Nrf2 pathway activity.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Genomics
Background:
- Chimeric antigen receptor (CAR) T-cell therapy has revolutionized hematologic cancer treatment but faces challenges in solid tumors like pancreatic ductal adenocarcinoma (PDAC).
- Understanding tumor-intrinsic resistance mechanisms is crucial for improving CAR T-cell therapy efficacy in PDAC, but current models are limited.
Purpose of the Study:
- To identify novel tumor-intrinsic modulators of CAR T-cell therapy response in pancreatic cancer.
- To investigate the role of oxidative and proteotoxic stress pathways in CAR T-cell resistance in PDAC.
Main Methods:
- Integrated modular CRISPR screening with immunocompetent orthotopic models of PDAC.
- Utilized single-cell gene expression analysis to characterize CAR T-cell resistant tumors.
- Investigated the mechanistic role of the Nrf2 pathway and its regulators (Keap1, Slc33a1) in modulating CAR T-cell sensitivity.
Main Results:
- Disruption of genes involved in oxidative and proteotoxic stress, specifically the Nrf2 target Slc33a1, sensitized PDAC tumors to CAR T-cell killing.
- CAR T-cell resistant tumors exhibited reduced Nrf2 pathway activity.
- Hyperactivation of the Nrf2 pathway, via Keap1 ablation or a tumor-derived Keap1 allele, sensitized PDAC tumors to CAR T-cell therapy.
Conclusions:
- Cell-intrinsic molecular states during malignant progression can sensitize tumor cells to cell-based immunotherapies like CAR T-cell therapy.
- Targeting oxidative and proteotoxic stress pathways, particularly the Nrf2 pathway, offers a potential strategy to enhance CAR T-cell efficacy in solid tumors.
- Tumor genotype may serve as a basis for patient stratification in CAR T-cell therapy for pancreatic cancer.
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