Similar Datasets
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.
2025-12-17 | GSE293373 | GEO
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.
2025-12-17 | GSE293372 | GEO
Project description:Coordinate tumor-antigen uptake and dendritic cell activation by chimeric antigen receptors.
| PRJNA1244298 | ENA
Project description:Coordinate tumor-antigen uptake and dendritic cell activation by chimeric antigen receptors. [RNA-seq]
| PRJNA1105880 | ENA
Project description:Coordinate tumor-antigen uptake and dendritic cell activation by chimeric antigen receptors. [TCR-seq]
| PRJNA1244302 | ENA
Project description:In recent years, chimeric antigen receptor (CAR) T cell cancer immunotherapies have advanced substantially in the clinic. However, challenges related to safety persist; one major concern occurs when CARs trigger a response to antigen present on healthy cells (on-target, off-tumor response). A strategy to ameliorate this relies on the complex relationship between receptor affinity and signaling, such that one can engineer a CAR that is only activated by tumor cells expressing high antigen levels. Here, we developed a CAR T cell display platform with stable genomic expression and rapid functional screening based on interleukin-2 signaling. Starting with a CAR with high affinity toward its target antigen, we combined CRISPR-Cas9 genome editing and deep mutational scanning to generate a library of antigen-binding domain variants. This library was subjected to multiple rounds of selection based on either antigen binding or cell signaling. Deep sequencing of the resulting libraries and a comparative analysis revealed the enrichment and depletion of specific variants from which we selected CARs that were selectively activated by tumor cells based on antigen expression levels. Our platform demonstrates how directed evolution based on functional screening and deep sequencing-guided selection can be combined to enhance the selectivity and safety of CARs.
| S-EPMC7704745 | biostudies-literature
Project description:Adoptive cellular therapy based on chimeric antigen receptor (CAR)-engineered T (CAR-T) cells is a powerful form of cancer immunotherapy. CAR-T cells can be redirected to specifically recognize tumor-associated antigens (TAAs) and induce high levels of antitumor activity. However, they may also display "on-target off-tumor" toxicities, resulting from low-level expression of TAAs in healthy tissues. These adverse effects have raised considerable safety concerns and limited the clinical application of this otherwise promising therapeutic modality. To minimize such side effects, we have designed an epidermal growth factor receptor (EGFR)-specific masked CAR (mCAR), which consists of a masking peptide that blocks the antigen-binding site and a protease-sensitive linker. Proteases commonly active in the tumor microenvironment can cleave the linker and disengage the masking peptide, thereby enabling CAR-T cells to recognize target antigens only at the tumor site. In vitro mCAR showed dramatically reduced antigen binding and antigen-specific activation in the absence of proteases, but normal levels of binding and activity upon treatment with certain proteases. Masked CAR-T cells also showed antitumor efficacy in vivo comparable to that of unmasked CAR. Our study demonstrates the feasibility of improving the safety profile of conventional CARs and may also inspire future design of CAR molecules targeting broadly expressed TAAs.
| S-EPMC5363190 | biostudies-literature
Project description:We describe a lentivirus-encoded chimeric receptor, termed extracellular vesicle (EV)-internalizing receptor (EVIR), which enables the selective uptake of cancer-cell-derived EVs by dendritic cells (DCs). The EVIR enhances DC presentation of EV-associated tumor antigens to CD8+ T cells primarily through MHCI recycling and cross-dressing. EVIRs should facilitate exploring the mechanisms and implications of horizontal transfer of tumor antigens to antigen-presenting cells.
| S-EPMC5833950 | biostudies-literature
Project description:Human cytomegalovirus (CMV) is a ubiquitous pathogen that causes significant morbidity in some vulnerable populations. Individualized adoptive transfer of ex vivo expanded CMV-specific CD8+ T cells has provided proof-of-concept that immunotherapy can be highly effective, but a chimeric antigen receptor (CAR) approach would provide a feasible method for broad application. We created 8 novel CARs using anti-CMV neutralizing antibody sequences, which were transduced via lentiviral vector into primary CD8+ T cells. All CARs were expressed. Activity against CMV-infected target cells was assessed by release of cytokines (interferon-γ and tumor necrosis factor-α), upregulation of surface CD107a, proliferation, cytolysis of infected cells, and suppression of viral replication. While some CARs showed varying functional activity across these assays, 1 CAR based on antibody 21E9 was consistently superior in all measures. These results support development of a CMV-specific CAR for therapeutic use against CMV and potentially other applications harnessing CMV-driven immunotherapies.
| S-EPMC7399702 | biostudies-literature
Project description:Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T cells to kill cancer. The success of CAR-T cell therapies highlights the promise of programmed immunity and suggests that applying CAR strategies to other immune cell lineages may be beneficial. Here, we engineered a family of Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that direct macrophages to engulf specific targets, including cancer cells. CAR-Ps consist of an extracellular antibody fragment, which can be modified to direct CAR-P activity towards specific antigens. By screening a panel of engulfment receptor intracellular domains, we found that the cytosolic domains from Megf10 and FcRɣ robustly triggered engulfment independently of their native extracellular domain. We show that CAR-Ps drive specific engulfment of antigen-coated synthetic particles and whole human cancer cells. Addition of a tandem PI3K recruitment domain increased cancer cell engulfment. Finally, we show that CAR-P expressing murine macrophages reduce cancer cell number in co-culture by over 40%.
| S-EPMC6008046 | biostudies-literature