Cytokine-armored dendritic cell progenitors for antigen-agnostic cancer immunotherapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA948418 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23958146.fastq.gz | Fastqsanger.gz | |||
| SRR23958147.fastq.gz | Fastqsanger.gz | |||
| SRR23958148.fastq.gz | Fastqsanger.gz | |||
| SRR23958149.fastq.gz | Fastqsanger.gz | |||
| SRR23958150.fastq.gz | Fastqsanger.gz |
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Project description:CAR‑T cell therapy is effective in hematologic malignancies but remains challenging in solid tumors owing to antigen heterogeneity and tumor microenvironment‑induced exhaustion. Here, gene editing of the nuclear receptor NR2F6 restores CAR‑T cell functionality, sustaining a TCF1⁺ progenitor‑exhausted T cell phenotype, enhancing metabolic fitness, and preserving cytotoxic potency under chronic antigen exposure. In immunocompetent models, Nr2f6‑deficient CAR‑T cells suppress solid tumor growth and induce robust, polyclonal host antitumor responses, as shown by protection in tumor re‑challenge experiments. Although infused CAR‑T cells disappear within 2 weeks, durable tumor control coincides with epitope spreading and secondary immune responses, likely via dendritic and other antigen‑presenting cell reactivation. Protection against antigen‑negative tumors and transferable immunity reveal a dual mode of direct cytotoxicity followed by durable immune reprogramming. This broadened host immunity may offset immune escape driven by antigen loss and tumor heterogeneity, establishing NR2F6 inhibition as a promising CAR‑T engineering strategy for durable, antigen‑agnostic solid‑tumor immunotherapy.
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Project description:Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors due to obstacles of antigen heterogeneity and the immunosuppressive tumor microenvironment (TME). Previous efforts focused on enhancing cytotoxicity and persistence of CAR T cells, while the feasibility of improving their therapeutic efficacy by leveraging the modulatory effects of CAR T cells on host anti-tumor immunity remains unclear. Here, we report that IL-36γ armored CAR T cells eradicated primary solid tumors and enabled rejection of rechallenged antigen-negative tumors. IL-36γ armored CAR T cells favorably modulated the TME and reprogrammed unique neutrophil subsets with tumoricidal ability and antigen-(cross)presenting functions, resulting in the induction of endogenous T cells recognizing tumor antigens beyond CAR-targeted antigens. Our study demonstrates that neutrophil engagement by CAR T cells is a critical step in the establishment of the cancer-immunity cycle and introduces a broadly applicable method to overcome key barriers to adoptive cell therapies for solid tumors.
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Project description:Effective anti-tumor immunity requires dendritic cells (DCs) to internalize, process and present tumor antigens to T cells. Adoptive transfer of DCs loaded ex vivo with tumor antigens has been shown to stimulate anti-tumor immunity in patients with cancer, but clinical responses have been mixed. To address limitations of traditional DC-based therapies, we constructed and functionally screened a panel of chimeric antigen receptors (CARs) optimized for expression and activity in DCs. Through this screening, we identified key functional components that informed the design of an inducible platform centered on an instructive chimeric antigen receptor (iCAR). This platform enables the DCs to (i) recognize a surface molecule present on cancer cells or their extracellular vesicles (EVs), such as GD2 and HER2, thereby promoting the acquisition of tumor-derived material that contains putative tumor antigens; (ii) undergo immunostimulatory activation to prime antigen-specific T cells via both cross-dressing and cross-presentation; and (iii) transactivate the expression of a therapeutic gene (IL-12) in response to antigen uptake. The iCAR converted melanoma-derived EVs from immune-suppressive to stimulatory cues for DCs. Moreover, systemic administration of iCAR-DCs enhanced antigen-specific T cells, expanded low-frequency T cell clonotypes, and delayed tumor growth in immunotherapy-resistant melanoma models without the need for ex vivo antigen loading or cell maturation. iCAR-DCs provide a platform for antigen-agnostic cancer immunotherapy that integrates antigen uptake with programmable DC activation.
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