Biology subjects

Debets, R.

Publications and source records attributed to Debets, R..

3 recordsLinked to original sources

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↗