Heterogeneity in the tumor microenvironment (TME) of follicular lymphomas (FLs) can affect clinical outcomes. Current immunotherapeutic strategies, including antibody- and cell-based therapies, variably overcome pro-tumorigenic mechanisms for sustained disease control. Modeling the intact FL TME, with its native, syngeneic tumor-infiltrating leukocytes, is a major challenge. Here, we describe an organoid culture method for cultivating patient-derived lymphoma organoids (PDLOs), which include cells from the native FL TME. We define the robustness of this method by successfully culturing cryopreserved FL specimens from diverse patients and demonstrate the stability of TME cellular composition, tumor somatic mutations, gene expression profiles, and B/T cell receptor dynamics over 3 weeks. PDLOs treated with CD3:CD19 and CD3:CD20 therapeutic bispecific antibodies showed B cell killing and T cell activation. This stable system offers a robust platform for advancing precision medicine efforts in FL through patient-specific modeling, high-throughput screening, TME signature identification, and treatment response evaluation.

中文翻译：

---

用于评估和靶向滤泡性淋巴瘤肿瘤免疫微环境的人类淋巴瘤类器官模型

滤泡性淋巴瘤 (FL) 的肿瘤微环境 (TME) 的异质性会影响临床结果。当前的免疫治疗策略，包括基于抗体和细胞的治疗，不同程度地克服了促肿瘤发生机制，以实现持续的疾病控制。对完整的 FL TME 及其天然同基因肿瘤浸润白细胞进行建模是一项重大挑战。在这里，我们描述了一种用于培养患者来源的淋巴瘤类器官（PDLO）的类器官培养方法，其中包括来自天然 FL TME 的细胞。我们通过成功培养来自不同患者的冷冻保存的 FL 标本来定义该方法的稳健性，并证明 TME 细胞组成、肿瘤体细胞突变、基因表达谱和 B/T 细胞受体动态在 3 周内的稳定性。用 CD3:CD19 和 CD3:CD20 治疗性双特异性抗体处理的 PDLO 显示 B 细胞杀伤和 T 细胞激活。这个稳定的系统提供了一个强大的平台，通过针对患者的建模、高通量筛选、TME 特征识别和治疗反应评估来推进 FL 的精准医疗工作。