在植入肿瘤异种移植物的造血人源化小鼠中对抗 PD-1 单药和联合免疫治疗的免疫反应特征。
Characterization of immune responses to anti-PD-1 mono and combination immunotherapy in hematopoietic humanized mice implanted with tumor xenografts.
机构信息
Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, 13001 E 17th Pl, Aurora, CO, 80045, USA.
Department of Immunology and Microbiology, School of Medicine, University of Colorado, Anschutz Medical Campus, 12800 E. 19th Ave P18-8401G, 13001 E 17th Pl, Aurora, CO, 80045, USA.
出版信息
J Immunother Cancer. 2019 Feb 8;7(1):37. doi: 10.1186/s40425-019-0518-z.
BACKGROUND
The success of agents that reverse T-cell inhibitory signals, such as anti-PD-1/PD-L1 therapies, has reinvigorated cancer immunotherapy research. However, since only a minority of patients respond to single-agent therapies, methods to test the potential anti-tumor activity of rational combination therapies are still needed. Conventional murine xenograft models have been hampered by their immune-compromised status; thus, we developed a hematopoietic humanized mouse model, hu-CB-BRGS, and used it to study anti-tumor human immune responses to triple-negative breast cancer (TNBC) cell line and patient-derived colorectal cancer (CRC) xenografts (PDX).
METHODS
BALB/c-Rag2Il2rγSIRPα (BRGS) pups were humanized through transplantation of cord blood (CB)-derived CD34+ cells. Mice were evaluated for human chimerism in the blood and assigned into experimental untreated or nivolumab groups based on chimerism. TNBC cell lines or tumor tissue from established CRC PDX models were implanted into both flanks of humanized mice and treatments ensued once tumors reached a volume of ~150mm. Tumors were measured twice weekly. At end of study, immune organs and tumors were collected for immunological assessment.
RESULTS
Humanized PDX models were successfully established with a high frequency of tumor engraftment. Humanized mice treated with anti-PD-1 exhibited increased anti-tumor human T-cell responses coupled with decreased Treg and myeloid populations that correlated with tumor growth inhibition. Combination therapies with anti-PD-1 treatment in TNBC-bearing mice reduced tumor growth in multi-drug cohorts. Finally, as observed in human colorectal patients, anti-PD-1 therapy had a strong response to a microsatellite-high CRC PDX that correlated with a higher number of human CD8+ IFNγ+ T cells in the tumor.
CONCLUSION
Hu-CB-BRGS mice represent an in vivo model to study immune checkpoint blockade to human tumors. The human immune system in the mice is inherently suppressed, similar to a tumor microenvironment, and thus allows growth of human tumors. However, the suppression can be released by anti-PD-1 therapies and inhibit tumor growth of some tumors. The model offers ample access to lymph and tumor cells for in-depth immunological analysis. The tumor growth inhibition correlates with increased CD8 IFNγ+ tumor infiltrating T cells. These hu-CB-BRGS mice provide a relevant preclinical animal model to facilitate prioritization of hypothesis-driven combination immunotherapies.
背景
逆转 T 细胞抑制信号的药物（如抗 PD-1/PD-L1 治疗）的成功，重新激发了癌症免疫治疗的研究。然而，由于只有少数患者对单药治疗有反应，因此仍然需要测试合理联合治疗的潜在抗肿瘤活性的方法。传统的鼠异种移植模型受到其免疫功能低下状态的限制；因此，我们开发了一种造血人源化小鼠模型 hu-CB-BRGS，并使用它来研究三阴性乳腺癌（TNBC）细胞系和患者来源的结直肠癌（CRC）异种移植（PDX）的抗肿瘤人类免疫反应。
方法
通过移植脐带血（CB）衍生的 CD34+细胞使 BALB/c-Rag2Il2rγSIRPα（BRGS）幼仔人源化。根据嵌合度评估血液中的人嵌合体，并将小鼠分配到未经治疗的实验组或纳武单抗组。将 TNBC 细胞系或已建立的 CRC PDX 模型的肿瘤组织植入人源化小鼠的两侧，一旦肿瘤体积达到约 150mm3，即进行治疗。每周测量肿瘤两次。研究结束时，收集免疫器官和肿瘤进行免疫评估。
结果
成功建立了具有高肿瘤植入率的人源化 PDX 模型。用抗 PD-1 治疗的人源化小鼠表现出增强的抗肿瘤人类 T 细胞反应，同时减少 Treg 和髓样细胞群，这与肿瘤生长抑制相关。在 TNBC 荷瘤小鼠中，与多药组相比，联合抗 PD-1 治疗可减少肿瘤生长。最后，与人类结直肠癌患者观察到的一样，抗 PD-1 治疗对微卫星高度不稳定的 CRC PDX 有强烈反应，与肿瘤中更多的人类 CD8+IFNγ+T 细胞相关。
结论
hu-CB-BRGS 小鼠代表了研究针对人类肿瘤的免疫检查点阻断的体内模型。小鼠中的人类免疫系统受到固有抑制，类似于肿瘤微环境，因此允许人类肿瘤生长。然而，抗 PD-1 治疗可以释放这种抑制并抑制一些肿瘤的生长。该模型为深入的免疫学分析提供了大量的淋巴和肿瘤细胞。肿瘤生长抑制与增加的 CD8 IFNγ+肿瘤浸润性 T 细胞相关。这些 hu-CB-BRGS 小鼠为促进假设驱动的联合免疫治疗提供了一个相关的临床前动物模型。
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