免疫檢查點阻斷可增強抗原特異DNA疫苗所誘發的抗癌效果及免疫

Abstract

本論文旨在研究抗原特異DNA疫苗合併阻斷PD-1或CTLA-4免疫檢查點之抗癌效果及其可能的作用機轉。利用帶有人類乳突病毒16型E6和E7抗原之鼷鼠同種腫瘤移植模式，探討anti-CTLA-4或anti-PD-1抗體是否會增強結締組織生長因子結合E7的嵌合DNA疫苗所誘發之抗原特異的抗癌效果及免疫反應以及可能的機轉。首先，anti-PD-1或anti-CTLA-4抗體合併E7抗原特異DNA疫苗的治療方式相較於單獨使用E7抗原特異之DNA疫苗治療，可以增加鼷鼠體內更強之anti-E7抗體、E7抗原特異之細胞毒性CD8 T淋巴球的數目及其細胞毒殺活性等抗原特異免疫力，以及抗癌效果。此外，在anti-PD-1或anti-CTLA-4抗體合併E7抗原特異DNA疫苗的治療下，鼷鼠體內全身性及腫瘤內的調節性T細胞數目都較單獨使用DNA疫苗的治療更低。更進一步的研究顯示anti-PD-1或anti-CTLA-4抗體合併E7抗原特異DNA疫苗的治療下，鼷鼠腫瘤內的樹突細胞之成熟狀態及其活化E7抗原特異之細胞毒性CD8 T細胞的能力都較單獨使用DNA疫苗的治療更強。總而言之，阻斷免疫檢查點的治療方式可以藉由克服腫瘤微環境內的免疫抑制狀態，以達到增強抗原特異DNA疫苗的抗原特異性之抗腫瘤免疫反應及抗癌效果。抗原特異性的免疫治療合併免疫檢查點的阻斷可以在臨床癌症治療上提供嶄新的治療策略。

I determined the antitumor effects and possible mechanisms of an antigen-specific DNA vaccine combined with PD-1 or CTLA-4 blockade. Using the HPV16 E6/E7+ syngeneic mouse tumor model, we investigated whether anti-CTLA-4 antibody (Ab) or anti-PD-1 Ab increases the antigen-specific antitumor effects and immune response induced by CTGF/E7 chimeric DNA vaccine and the possible mechanisms. Anti-PD-1 Ab or anti-CTLA-4 Ab combined with E7-specific DNA vaccine generated more potent antigen-specific immunity, including anti-E7 Abs and the number and cytotoxic activity of E7-specific cytotoxic CD8+ T lymphocytes, and antitumor effects than E7-specific DNA vaccine alone. In addition, the number of systemic and intratumoral Tregs was lower with the anti-PD-1 or anti-CTLA-4 Ab and E7-specific DNA vaccine. Furthermore, anti-PD-1 and anti-CTLA-4 Abs could enhance the maturation and abilities of intratumoral DCs to activate E7-specific cytotoxic CD8+ T cells. I conclude that immune checkpoint blockade could overcome the immunosuppressive status of the tumor microenvironment to enhance the antigen-specific immunity and antitumor effects generated by an antigen-specific DNA vaccine. Antigen-specific immunotherapy combined with immune checkpoint blockade can be a novel strategy in clinical cancer therapy.