Abstract
"肝癌是第六大最常見的癌症，每年在全世界造成約80萬例死亡。接受傳統療法的肝癌患者的平均五年生存率仍低於30％。因此近來發展的T細胞輸入療法成為肝癌患者的新希望。一個成功的T細胞療法必須能克服肝腫瘤微環境的免疫抑制性，以達到顯著抗腫瘤功效。
先前的研究我們發現在自發性肝細胞癌小鼠模型中，高表達Akt2的毒殺型T細胞有優異的抗腫瘤能力。Akt訊息傳遞不僅增強了毒殺型T細胞功能，如細胞毒殺能力，也抑制了某些免疫檢查點的表達，並促進組織常駐記憶型T細胞的分化。這些數據促使我們將進一步研究Akt2訊息傳遞如何使毒殺型T細胞克服肝腫瘤微環境的免疫抑制性並消除癌細胞。我們假設PI3K / Akt訊息傳遞會影響與記憶型T細胞之分化及免疫檢查點有關的轉錄調控。加上已知Akt能增強T細胞功能，因而高表達Akt2 的毒殺型T細胞能迅速攻擊腫瘤細胞並將肝腫瘤微環境轉變為發炎狀態。發炎環境所產生的因子可進一步將預先編程的Akt2毒殺型T細胞分化成肝內CXCR6+LFA1+組織常駐記憶型T細胞。我們在子計畫5中將研究：
1）肝腫瘤微環境中Akt2訊息傳遞如何影響組織常駐記憶型T細胞分化的詳細機制。
2）Akt2訊息傳遞如何調節免疫檢查點表達。
3）T細胞治療前後肝腫瘤微環境中淋巴球與骨髓衍生/基質細胞群的數量和功能變化。
4）發展新穎肝癌T細胞療法 。
我們相信這項研究將促進我們對毒殺型T細胞之存活，效能及分化的了解，這將促進肝癌的CAR T細胞療法之發展。"
"Liver cancer is the sixth most common cancer and causes approximately 800,000 deaths annually worldwide. The average five-year survival rate of HCC patients receiving traditional therapies is still below 30%. The emerging T-cell based cancer therapy becomes a new hope to HCC patient. A successful adoptive T-cell therapy has to overcome immunosuppressive HCC tumor microenvironment to achieve high anti-tumor efficacy.
In our previous study, we found that Akt2-overexpressed but not control or Akt1-overexpressed tumor Ag-specific CTLs exhibited superior anti-tumoral capabilities in a spontaneous HCC mouse model. Akt signaling in CTLS not only enhanced their effector functions e.g. cytotoxicity but suppressed the expression of certain immune checkpoints and promoted the differentiation of tissue resident memory T (TRM) cells in the tumor. These data motivate us to further study how the Akt2 signaling enables the CTLs to overcome HCC TME and eliminate cancer cells in this sub-project. We therefore hypothesize that PI3K/Akt signaling influences the transcriptional regulation related to memory T-cell differentiation and immune checkpoint expression. In combination to the enhanced effector function, the Akt2-overexpressed CTLs rapidly attack tumor cells and turn the HCC TME into inflammatory. The inflammatory milieu further drives the pre-programmed Akt2-CTLs into CXCR6+LFA1+ liver TRM cells. We propose in sub-project 5 to study
1) the detailed mechanisms of Akt2-triggered TRM differentiation in HCC TME;
2) the regulation of immune checkpoint expression by Akt signaling;
3) the quantitative and functional changes of lymphoid and myeloid/stromal cell
population in the TME of HCC before and after adoptive T-cell therapy and
4) the development of novel adoptive T-cell therapy for treatment of HCC.
We believe that this research will improve our understanding on regulation of survival, effector functions and differentiation of adoptively transferred CTLs, which will facilitate the development of effective immunotherapies including CAR T-cell therapies against HCC as the ultimate goal of this sub-project."
Keyword(s)
肝癌
腫瘤微環境
免疫檢查點
細胞療法
hepatocellular carcinoma
tumor microenvironment
immune checkpoint
cell therapy
