在癌症免疫治疗中表征肝细胞癌反应性和难治性原位小鼠模型。,PLOS ONE

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在癌症免疫治疗中表征肝细胞癌反应性和难治性原位小鼠模型。
PLOS ONE ( IF 2.9 ) Pub Date : 2019-07-10 , DOI: 10.1371/journal.pone.0219517
Carina Hage _{1,

2} , Sabine Hoves ₁ , Mailin Ashoff ₁ , Veronika Schandl ₁ , Stefan Hört ₁ , Natascha Rieder ₁ , Christian Heichinger ₃ , Marco Berrera ₃ , Carola H Ries ₁ , Fabian Kiessling ₂ , Thomas Pöschinger ₁

Affiliation

肝细胞癌（HCC）是世界上最常见的癌症之一，由于治疗选择有限，因此死亡率很高。因此，在临床试验中对HCC对不同癌症免疫疗法的反应进行了深入研究。免疫检查点阻滞剂（ICB）表现出可喜的结果，尽管对少数HCC患者而言。小鼠模型通常用于评估新的治疗剂或治疗方案。但是，为了使临床翻译更成功，需要更好地表征的临床前模型。因此，我们就形态，免疫学和遗传学特征广泛研究了两种具有免疫功能的原位HCC小鼠模型，即移植的Hep-55.1c和转基因iAST，并评估了这两种模型对免疫疗法的反应性。Hep-55。1c肿瘤的特点是纤维基质丰富，突变负荷高和明显的免疫细胞浸润，所有这些都是免疫反应性肿瘤的特征。尽管这些特征高度血管化，但在iAST肿瘤中这些特征不太明显。细胞耗竭显示，来自iAST小鼠的CD8 + T细胞不影响肿瘤生长，并且具有肿瘤耐受性。这对应于针对PD-1和CTLA-4的单个和组合ICB的故障。相反，在Hep-55.1c小鼠模型中，组合使用抗PD-1和抗CTLA-4显示出显着的抗肿瘤功效。总的来说，我们的数据全面表征了两种具有免疫功能的HCC小鼠模型，这些模型代表了ICB反应性和难治性特征。

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Characterizing responsive and refractory orthotopic mouse models of hepatocellular carcinoma in cancer immunotherapy.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a high mortality rate due to limited treatment options. Hence, the response of HCC to different cancer immunotherapies is being intensively investigated in clinical trials. Immune checkpoint blockers (ICB) show promising results, albeit for a minority of HCC patients. Mouse models are commonly used to evaluate new therapeutic agents or regimens. However, to make clinical translation more successful, better characterized preclinical models are required. We therefore extensively investigated two immune-competent orthotopic HCC mouse models, namely transplanted Hep-55.1c and transgenic iAST, with respect to morphological, immunological and genetic traits and evaluated both models' responsiveness to immunotherapies. Hep-55.1c tumors were characterized by rich fibrous stroma, high mutational load and pronounced immune cell infiltrates, all of which are features of immune-responsive tumors. These characteristics were less distinct in iAST tumors, though these were highly vascularized. Cell depletion revealed that CD8+ T cells from iAST mice do not affect tumor growth and are tumor tolerant. This corresponds to the failure of single and combined ICB targeting PD-1 and CTLA-4. In contrast, combining anti-PD-1 and anti-CTLA-4 showed significant antitumor efficacy in the Hep-55.1c mouse model. Collectively, our data comprehensively characterize two immune-competent HCC mouse models representing ICB responsive and refractory characteristics. Our characterization confirms these models to be suitable for preclinical investigation of novel cancer immunotherapy approaches that aim to either deepen preexisting immune responses or generate de novo immunity against the tumor.

更新日期：2019-07-10

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