肿瘤细胞治疗研究
英文原题：Evaluation of tumor response to immune checkpoint inhibitors by a 3D immunotumoroid model.
Evaluation of tumor response to immune checkpoint inhibitors by a 3D immunotumoroid model.
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我们的免疫肿瘤类器官模型充分复现了肿瘤微环境的多细胞特性，足以用于临床前 ICI 筛选。
肾癌和膀胱癌患者中仅约20%对免疫检查点抑制剂（ICI）治疗有显著应答，目前也没有可准确预测ICI应答的检测方法。
我们建立“免疫肿瘤球”细胞模型，在患者来源球体中重现肿瘤、微环境和必要免疫系统成分，以便离体评估肿瘤对ICI的应答。模型由手术切除的肾细胞癌和膀胱癌制备，筛选TIL（肿瘤浸润淋巴细胞）水平较高的样本；其在不更换培养基的情况下可存活超过1个月。采用免疫组化检测冷冻保存的原发肿瘤及相应免疫肿瘤球中的免疫和非免疫细胞。使用Incucyte设备和Cytotox Red染色实时监测免疫肿瘤球对ICI（nivolumab、pembrolizumab和durvalumab）及化疗药（cisplatin、gemcitabine和paclitaxel）的反应，并与回顾性临床药物应答比较。
13例病例中有6例成功培养出存活的免疫肿瘤球模型；失败原因包括肿瘤组织广泛坏死或淋巴细胞过多导致球体无法形成。1例成功培养病例因原发肿瘤样本TIL浸润低（<5%）而排除。其余5个模型含有免疫细胞（CD4⁺和CD8⁺ T细胞、巨噬细胞）、非免疫细胞（成纤维细胞）及肿瘤细胞。在5例免疫肿瘤球中测试化疗药和ICI，并在有临床数据时比较治疗结局。4/5个模型对化疗出现细胞杀伤反应，2/5个模型对ICI敏感。在3例病例中，免疫肿瘤球模型准确预测了患者对ICI或化疗的临床应答或无应答。
免疫肿瘤球模型充分重现了肿瘤微环境的多细胞特征，可用于临床前ICI筛选。该模型有助于深入理解癌细胞、免疫系统和微环境之间的复杂相互作用。本研究仅为少数病例的可行性研究，仍需开展更大样本研究并与临床应答相关联。
Only 20 percent of renal and bladder cancer patients will show a significant response to immune checkpoint inhibitor (ICI) therapy, and no test currently available accurately predicts ICI response.
We developed an "immunotumoroid" cell model system that recapitulates the tumor, its microenvironment, and necessary immune system components in patient-derived spheroids to enable ex vivo assessment of tumor response to ICI therapy. Immunotumoroids were developed from surgically resected renal cell carcinomas and bladder carcinomas selected for high tumor-infiltrating lymphocytes (TILs) and survived more than a month without media exchange. Immunohistochemistry was used to detect immune and non-immune cells in cryopreserved source tumors and the resulting immunotumoroids. Immunotumoroid response to ICIs (nivolumab, pembrolizumab, and durvalumab) and chemotherapy (cisplatin, gemcitabine, and paclitaxel) was monitored in real-time with Cytotox Red staining in an Incucyte device, and the immunotumoroid response was compared to retrospective clinical drug responses.
Six of the 13 cases tested grew viable immunotumoroid models, with failed cases attributed to extensive tumor tissue necrosis or excess lymphocytes preventing spheroid formation. One successfully cultured case was excluded from the study due to low TIL infiltration (<5%) in the primary tumor sample. The five remaining models contained immune cells (CD4+ and CD8+ T cells, and macrophages), non-immune cells (fibroblasts), and tumor cells. Chemotherapy and ICI drugs were tested in immunotumoroids from 5 cases and compared to clinical outcomes where data was available. Four/five models showed cell killing in response to chemotherapy and two/five showed sensitivity to ICI. In three cases, the immunotumoroid model accurately predicted the patient's clinical response or non-response to ICIs or chemotherapy.
Our immunotumoroid model replicated the multicellular nature of the tumor microenvironment sufficiently for preclinical ICI screening. This model could enable valuable insights into the complex interactions between cancer cells, the immune system, and the microenvironment. This is a feasibility study on a small number of cases, and additional studies with larger case numbers are required including correlation with clinical response.
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