Biology subjects

Debets, R.

Publications and source records attributed to Debets, R..

5 recordsLinked to original sources

bioRxiv2025

Adoptive cell therapy using T cell receptors equipped with ICOS yields durable anti-tumor response

Treatment with adoptively transferred T cells is challenged by limited longevity of therapeutic cells within tumors. To enhance the durability of anti-tumor T cell products, we have created T cell receptors (TCRs) with built-in co-stimulatory molecules. We observed that TCRs coupled to ICOS mediated exceptionally long-term responses including delay of tumor recurrence and cures in a mouse tumor model. TCR:ICOS T cells showed enhanced and antigen-specific production of inflammatory cytokines and resistance to exhaustion. Genetic ablation of ICOS-mediated activation of the PI3K-NF{kappa}B pathway neutralized the long-term anti-tumor effects. To translate TCR:ICOS to human T cells, we identified a single amino acid change in the cytosolic tail which was necessary for functional surface expression. Notably, the optimized receptor sustained performance of human T cells upon repeated stimulation across multiple antigen specificities. Collectively, we present a novel and uniformly applicable TCR:ICOS format that supports fitter T cell products for adoptive cell therapy. HighlightsNewly designed co-stimulatory TCR, with extracellular TCR-V and C domains coupled to CD28 transmembrane domain, and ICOS and CD3{varepsilon} intracellular domains (in short TCR:ICOS) provides:[tpltrtarr] durable anti-tumor response and T cell persistence in mouse model [tpltrtarr]inflammatory T cell phenotype and resistance to T cell exhaustion [tpltrtarr]effects via PI3K and NF{kappa}B activation [tpltrtarr]translation to human T cells upon single amino acid mutation in TCR:ICOS tail [tpltrtarr]extension to multiple clinically relevant TCRs while preserving prolonged T cell fitness O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/682056v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1ff752borg.highwire.dtl.DTLVardef@6579d9org.highwire.dtl.DTLVardef@22bdc4org.highwire.dtl.DTLVardef@d8c445_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

CLEAR-IT: Contrastive Learning Enabled Accurate Registration of Immune and Tumor cells from multiplexed images with limited labels in a platform-independent manner

Accurate phenotyping of cells in the tumor microenvironment is crucial for understanding cancer biology and developing effective therapies. However, current methods require precise cell segmentations and struggle to generalize across different imaging modalities, limiting their utility in digital pathology. Here, we show that Contrastive Learning Enabled Accurate Registration of Immune and Tumor Cells (CLEAR-IT) overcomes these limitations, providing a robust and versatile tool for cell phenotyping. CLEAR-IT accurately phenotypes cells comparable to state-of-the-art methods, generalizes across multiplex imaging modalities, maintains high performance even with limited number of labels, and enables the extraction of prognostic markers. Additionally, CLEAR-IT can be combined with existing methods to boost their performance, whereas its lack of need for precise cell segmentations significantly reduces training efforts. This method enhances the robustness and efficiency of digital pathology workflows, making it a valuable tool for cancer research and diagnostics.

bioinformatics↗

bioRxiv2024

TCR-engineered T-cells directed against Ropporin-1 constitute a safe and effective treatment for triple-negative breast cancer in near-clinical models

Triple-negative breast cancer (TNBC) shows an urgent need for new therapies. We discovered Ropporin-1 (ROPN1) as a target to treat TNBC with T-cells. ROPN1 showed high and homogenous expression in 90% of primary and metastatic TNBC but not in healthy tissues. HLA-A2-binding peptides were detected via immunopeptidomics and predictions and used to retrieve T-cell receptors (TCRs) from naive repertoires. Following gene introduction into T-cells and stringent selection, we retrieved a highly specific TCR directed against the epitope FLYTYIAKV that did not recognize non-cognate epitopes from alternative source proteins. Notably, this TCR mediated killing of three-dimensional tumoroids in vitro and tumor cells in vivo and outperformed standard-of-care drugs. Finally, the T-cell product expressing this TCR and manufactured using a clinical protocol fulfilled standard safety and efficacy assays. Collectively, we have identified and preclinically validated ROPN1 as a target and anti-ROPN1 TCR T-cells as a treatment for the vast majority of TNBC patients.

immunology↗

bioRxiv2022

T Cell-to-Stroma Enrichment (TSE) score: a gene expression metric that predicts response to immune checkpoint inhibitors in patients with urothelial cancer

Immune checkpoint inhibitors (ICIs) improve overall survival in patients with metastatic urothelial cancer (mUC). To identify predictive markers of response, whole-genome DNA (n=70) and RNA-sequencing (n=41) were performed using fresh metastatic biopsies prior to treatment with pembrolizumab. PD-L1 combined positivity score did not, whereas tumor mutational burden and APOBEC mutagenesis modestly predicted response. Using gene expression analysis, we defined the T cell-to-stroma enrichment (TSE) score, a signature-based metric that captures the relative abundance of T cells and stromal cells. Patients with a positive and negative TSE score show progression-free survival rates at 6 months of 67 and 0%, respectively. The TSE score was captured by immunofluorescence in tumor tissue, and validated in two independent ICI-treated cohorts of patients with mUC (IMvigor210) and muscle-invasive UC (ABACUS). In conclusion, the TSE score represents a clinically applicable marker that potentially aids in prospectively selecting patients with mUC for ICI treatment.

cancer biology↗

bioRxiv2020

Transient cell-in-cell formation underlies tumor resistance to immunotherapy

Despite the remarkable success of immunotherapy in cancer, most patients will develop resistant tumors. While the main conceptual paradigm suggests that relapsed clones emerge through a process of clonal selection and immunoediting, currently little evidence directly demonstrates this process in epithelial cancers. To study this process, we established several mouse models in which tumors drastically regress following immunotherapy, yet resistant tumors relapse within a few weeks of treatment cessation. Whole exome analyses indicated that relapsed tumors share hundreds of neo-antigens with the primary tumors and are comparably killed by reactive T cells. Examination of tumor cells that survive immunotherapies revealed that they structure a transient cell-in-cell formation, which is impenetrable to immune-derived cytotoxic compounds and to chemotherapies. This formation is mediated predominantly by a cell-membrane protein on activated T cells, which subsequently induces epidermal growth factor receptors and STAT3 phosphorylation in tumors cells. In contrast to previous reports on cell-in-cell formations, here both cells remain alive and can disseminate into single tumor cells once T cells are no longer present. Overall, this work highlights a powerful resistance mechanism which enable tumor cells to survive immune pressure and provides a new theoretical framework for combining chemotherapies and immunotherapies.

immunology↗