A patient-derived T cell lymphoma biorepository uncovers pathogenetic mechanisms and host-related therapeutic vulnerabilities.

Peripheral T cell lymphomas (PTCLs) comprise heterogeneous malignancies with limited therapeutic options. To uncover targetable vulnerabilities, we generate a collection of PTCL patient-derived tumor xenografts (PDXs) retaining histomorphology and molecular donor-tumor features over serial xenografting. PDX demonstrates remarkable heterogeneity, complex intratumor architecture, and stepwise trajectories mimicking primary evolutions. Combining functional transcriptional stratification and multiparametric imaging, we identify four distinct PTCL microenvironment subtypes with prognostic value. Mechanistically, we discover a subset of PTCLs expressing Epstein-Barr virus-specific T cell receptors and uncover the capacity of cancer-associated fibroblasts of counteracting treatments. PDXs' pre-clinical testing captures individual vulnerabilities, mirrors donor patients' clinical responses, and defines effective patient-tailored treatments. Ultimately, we assess the efficacy of CD5KO- and CD30- Chimeric Antigen Receptor T Cells (CD5KO-CART and CD30_CART, respectively), demonstrating their therapeutic potential and the synergistic role of immune checkpoint inhibitors for PTCL treatment. This repository represents a resource for discovering and validating intrinsic and extrinsic factors and improving the selection of drugs/combinations and immune-based therapies.