在原發性肝癌小鼠探討肝癌臨床用藥結合免疫療法對腫瘤抗原特異性T細胞的影響

The effects of Lenvatinib combined with anti-PD1 on antigen-specific T cells in spontaneous hepatocellular carcinoma mouse model

林奕萱(Yi-Hsuan Lin)

指導教授 ： 楊宏志

國立臺灣大學/醫學院/微生物學研究所/碩士(2020年)

https://doi.org/10.6342/NTU202003234

摘要

原發性肝癌是目前全球各種癌症致死率的第二名，而其中肝細胞性肝癌又占了80到90%的原發性肝癌，常見的臨床用藥治療主要是依據巴塞隆納肝癌分級來決定治療方式，依據病人的體能狀態以及腫瘤大小能夠將病人分為初期及末期，由於大部分肝癌病人在確診時通常都已經是接近末期階段，因此在此階段使用的標靶治療是大家共同研究的目標，近年來，合併使用標靶治療以及免疫療法已經成為新興的研究領域，日前美國食藥署即公布，根據臨床試驗第3期結果已核准使用作為肝細胞肝癌的一線用藥，然而其中對於合併治療的機制以及免疫反應尚未清楚。在探討用藥的免疫反應尤其重要的是建立一個理想的小鼠模型來研究其中腫瘤微環境以及免疫細胞的相互作用，因此，我們使用了尾部靜脈高壓注射技術建立了原發性肝癌小鼠模型，並以肝炎病毒的分泌性膜蛋白(HBsAg)作為監測腫瘤生長的標的，接著送入能夠辨認特異性抗原的T細胞來研究在肝癌環境當中的免疫環境，根據結果我們發現在腫瘤初期時送入CD8 T細胞能夠有效清除腫瘤，然而在腫瘤較為後期時，送入T細胞仍無法控制腫瘤，並且造成T細胞衰竭，因此我們希望結合合併藥物治療來加強T細胞的功能並達到清除腫瘤的目標。

關鍵字

原發性肝癌小鼠模型 ； 合併免疫治療 ； 抗原特異性T細胞

並列摘要

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, accounting for 80-90% cases and the prognosis of unresectable HCC (uHCC) is poor. Interestingly, combination immunotherapy with immune-checkpoint inhibitor (ICI) and target therapy has yielded very promising results for treatment of uHCC. Recently, FDA has approved atezolizumab (anti-PDL1) in combination with bevacizumab (anti-VEGF) for the treatment of people with unresectable or metastatic HCC who have not received prior systemic therapy. The immune response and the mechanism of the combinatory remained unknown. Here, we successfully developed a HDI-based spontaneous HCC model to study the antigen-specific T cell response. The HBsAg-HCC model was induced through the HBsAg-Nras-OVAI/II and PTEN-p53/Cas9 plasmids. The expression level of HBsAg could be detected periodically and used to monitor the tumor growth. Our data showed that adoptively transferring naïve CD8 T cells to early-staged tumor could eradicate the tumors. However, the naïve CD8 T cells transferred to late-staged tumors could not control the tumor growth. Additionally, Ag-specific CD8 T cells mostly became liver resident cells and expressed the exhaustion phenotype. The result rendered us the new insight to develop the T cell based therapy combined with target therapy to improve the anti-tumor immunity.

並列關鍵字

spontaneous HCC model ； immune-based combinatory therapy ； Ag-specific T cell

參考文獻

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