肿瘤细胞治疗研究
英文原题：A patient-derived T cell lymphoma biorepository uncovers pathogenetic mechanisms and host-related therapeutic vulnerabilities.
外周 T 细胞淋巴瘤（PTCL）是一组异质性恶性肿瘤，治疗选择有限。
外周 T 细胞淋巴瘤（PTCL）是一组异质性恶性肿瘤，治疗选择有限。为发现可靶向的弱点，研究者建立了一组 PTCL 患者来源肿瘤异种移植模型（PDX）；这些模型在连续异种移植过程中保留组织形态和供者肿瘤分子特征。PDX 显示出显著异质性、复杂的瘤内结构以及模拟原发肿瘤演化的阶段性轨迹。结合功能性转录分层和多参数成像，研究者识别出 4 种具有预后价值的独特 PTCL 微环境亚型。在机制方面，研究者发现一部分 PTCL 表达 EB 病毒特异性 T 细胞受体，并揭示癌相关成纤维细胞可抵消治疗作用。PDX 临床前测试能够捕捉个体弱点、反映供者患者的临床应答，并确定有效的个体化治疗。最后，研究者评估了 CD5 敲除和 CD30 CAR-T 细胞（分别为 CD5KO-CART 和 CD30_CART）的疗效，证明其具有治疗潜力，且免疫检查点抑制剂在 PTCL 治疗中可发挥协同作用。该模型库可用于发现和验证内在及外在因素，并改进药物/联合疗法和免疫治疗的选择。
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.
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