E0771.syngeneic breast cancer model

三重阴性乳腺癌（TNBC）是缺乏雌激素受体，孕酮受体和HER2扩增的复杂和侵蚀性亚型;使其难以治疗。因此，对TNBC更好的治疗方案有持续的需求。为了帮助解决TNBC型号的需求，我们突出了EMT6模型last month and herein we put forth theE0771.model, another TNBC syngeneic model for use in preclinical immuno-oncology. The E0771 cell line is a spontaneously developing medullary breast adenocarcinoma from C57BL/6 mice.[1] Parental E0771 is poorly metastatic when compared to 4T1[2] and has homozygous mutations in theTRP53andKRAS基因。[3]

在这个聚光灯中，我们将数据从我们的初始增长和功效研究中展示了E0771模型。The data presented here provides an overview of the E0771 cell line’s response to免疫肿瘤学agents andradiation therapy实现理性组合研究的设计。

E0771模型的肿瘤生长动力学如图1所示。中值倍增时间为〜5-6天，肿瘤体积稳步增加，没有明显的肿瘤相关体重减轻。生长速率允许三周治疗窗口评估抗​​肿瘤反应。未处理肿瘤和同种型对照（大鼠IgG2B）处理的肿瘤的生长参数类似（图1）。

Composition of Tumor Infiltrating Immune Cells

分析基线肿瘤免疫组合物流式细胞仪and is shown in Fig. 2. The immune profile for E0771 was established from tumors ~750mm3 in volume. The tumors have a high CD45+ cell (70%) infiltration of which the T-cell population (CD8+ T cells and CD4+ T helper cells) are well represented (6% each). The Treg population was consistently lower than the CD4+ T helper cell or CD8+ T cell population. Within the myeloid population, E0771 tumors are unique among our characterized breast cancer lines in having an abundance of M-MDSCs and a near absence of G-MDSCs. M1 macrophages were consistently lower than M2 macrophages in the tumors analyzed. This composition is suggestive of an immunosuppressive microenvironment.

Responses to Treatments

免疫调节药物反应是评估on mice bearing E0771 tumors treated with checkpoint blockade antibodies (anti-mPD-1, anti-mPD-L1, anti-mCTLA-4, and anti-mLAG3), costimulatory antibodies (anti-mGITR, anti-mOX40, and anti-mCD137) and focal radiation. We tested anti-tumor response to checkpoint inhibitors and costimulatory antibodies in which dosing was initiated prior to palpable tumor formation (Fig. 3). Anti-mPD-1 treatment resulted in complete elimination of the tumor, while anti-mPD-L1 and anti-mLAG3 had significant responses with tumor growth delay (TGD) of 12.7 and 7.6 days respectively (Fig. 3A). Likewise, treatment with costimulatory antibodies anti-mGITR, anti-mCD137, and anti-mOX40 elicited substantial responses with over 50% tumor free survivors (TFSs) and TGD >27 days (Fig. 3B).

虽然这些结果清楚地表明E0771对免疫疗法的反应性（图5），同时强调肿瘤体积等因素对结果的治疗方案时的重要性。免疫抑制微环境可以帮助解释测试的大多数免疫疗法方案的有限反应。焦点辐射可以是改性免疫抑制微环境的有用治疗方式。因此，测试局灶性辐射剂量5,10和20Gy，发现分别具有5.1,6.0和10.6天的TGD耐受良好的耐受性（图6）。基于基线辐射剂量响应数据，可以建议10Gy焦辐射进行组合疗法。

E0771.– A Powerful Preclinical Immuno-Oncology Breast Cancer Model

TNBC通常对具有免疫疗法的单一疗法有抵抗，并且由于其最小的肿瘤CD8 + T细胞渗透和由于低突变负担而低免疫原性而被视为免疫“冷”癌症。鉴于适得良好的免疫细胞浸润和对免疫疗法的反应，E0771 Syngeenecic乳腺癌模型作为临床前免疫肿瘤学模型提供了显着的潜力。yaboapp体育官网我们的数据概述了每个单药治疗的效果，并告知设计组合策略。治疗开始时间和肿瘤量在确定结果的动态方面发挥着关键作用，并且应该使用E0771模型在研究设计中进行强烈考虑。

Pleasecontact Covanceto speak with our scientists about how E0771, or one of our other同工模型，可用于您的下一个免疫肿瘤学研究。