Department of Medical Oncology, Catalan Institute of Oncology (ICO-L'Hospitalet), Barcelona, Spain.
Department of Oncology, Livestrong Cancer Institutes, Dell Medical School, University of Texas at Austin, Austin, TX, United States.
Front Immunol. 2021 Mar 29;12:607282. doi: 10.3389/fimmu.2021.607282. eCollection 2021.
Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-administration of other agents. Preclinical, small-animal models are strongly desired to increase the pace of scientific discovery, while reducing the cost of combination drug testing in humans. Human immune system (HIS) mice are highly immune-deficient mouse recipients rtpeconstituted with human hematopoietic stem cells. These HIS-mice are capable of growing human tumor cell lines and patient-derived tumor xenografts. This model allows rapid testing of multiple, immune-related therapeutics for tumors originating from unique clinical samples. Using a cord blood-derived HIS-BALB/c-Rag2Il2rγSIRPα (BRGS) mouse model, we summarize our experiments testing immune checkpoint blockade combinations in these mice bearing a variety of human tumors, including breast, colorectal, pancreatic, lung, adrenocortical, melanoma and hematological malignancies. We present in-depth characterization of the kinetics and subsets of the HIS in lymph and non-lymph organs and relate these to protocol development and immune-related treatment responses. Furthermore, we compare the phenotype of the HIS in lymph tissues and tumors. We show that the immunotype and amount of tumor infiltrating leukocytes are widely-variable and that this phenotype is tumor-dependent in the HIS-BRGS model. We further present flow cytometric analyses of immune cell subsets, activation state, cytokine production and inhibitory receptor expression in peripheral lymph organs and tumors. We show that responding tumors bear human infiltrating T cells with a more inflammatory signature compared to non-responding tumors, similar to reports of "responding" patients in human immunotherapy clinical trials. Collectively these data support the use of HIS mice as a preclinical model to test combination immunotherapies for human cancers, if careful attention is taken to both protocol details and data analysis.
在过去的十年中，免疫疗法彻底改变了癌症的治疗方式。尽管免疫疗法的成功引人注目，但它仍然局限于一部分患者。目前有超过 1500 项临床试验正在进行，旨在通过联合使用其他药物来提高免疫疗法的疗效。临床前的小动物模型强烈需要加快科学发现的步伐，同时降低在人体中进行组合药物测试的成本。人免疫系统（HIS）小鼠是高度免疫缺陷的小鼠受体，用人类造血干细胞重新构建。这些 HIS 小鼠能够生长人肿瘤细胞系和患者来源的肿瘤异种移植物。这种模型允许快速测试来自独特临床样本的多种与免疫相关的治疗药物。使用源于脐带血的 HIS-BALB/c-Rag2Il2rγSIRPα（BRGS）小鼠模型，我们总结了我们在这些携带各种人类肿瘤的小鼠中测试免疫检查点阻断联合治疗的实验，包括乳腺癌、结直肠癌、胰腺癌、肺癌、肾上腺皮质癌、黑色素瘤和血液恶性肿瘤。我们深入描述了 HIS 在淋巴和非淋巴器官中的动力学和亚群，并将这些与方案开发和免疫相关的治疗反应联系起来。此外，我们比较了 HIS 在淋巴组织和肿瘤中的表型。我们表明，肿瘤浸润白细胞的免疫表型和数量变化很大，并且在 HIS-BRGS 模型中这种表型是肿瘤依赖性的。我们进一步展示了外周淋巴器官和肿瘤中免疫细胞亚群、激活状态、细胞因子产生和抑制性受体表达的流式细胞术分析。我们表明，与非应答性肿瘤相比，应答性肿瘤具有更多炎症特征的人浸润 T 细胞，与人类免疫治疗临床试验中“应答”患者的报告相似。这些数据共同支持将 HIS 小鼠用作测试针对人类癌症的联合免疫疗法的临床前模型，如果仔细注意方案细节和数据分析。
