Abstract
摘要:犬隻癌症乃目前犬死亡率之首。在腫瘤之中,僅少部分腫瘤對化療藥物有所反應,大部份腫瘤所具有的 multidrug resistance 特性,常有效抵抗化療藥物的治療。再者,化療藥物對動物體具有毒性,往往限制其應用價值。此外,腫瘤常使用一種以上的機制逃避宿主的免疫攻擊,包括降低 MHC 的表現或分泌各種細胞激素,以抑制一系列的免疫反應,使體內免疫細胞無法有效辨識腫瘤相關及特異性抗原(tumor associated antigens),進而發展為免疫耐受性(immune tolerance)。因此, 若能有效活化免疫系統,使其重新恢復辨識腫瘤相關抗原之能力,則可對腫瘤進行毒殺作用,此方法已成為癌症免疫治療之重要課題。免疫療法相較於傳統之化療藥物更能有效的針對腫瘤進行專一性的毒殺作用,其副作用相對減少,然而免疫療法的治療效果仍然有限。究其原因乃是腫瘤在生長過程中會積極建立有利於它的微環境及防禦牆,包括形成 cytokine network 及 stroma barrier,有效降低患者免疫細胞的功能。若要有效突破目前免疫療法的困境,除了必須加強腫瘤抗原的呈現外,破壞其微環境及防禦牆則為必要。因此本研究第一部分便是針對體內最有效之抗原呈現細胞---樹突狀細胞(DC)進行相關研究,強化對腫瘤抗原辨識的能力。第二部分,將針對腫瘤細胞做更基礎的研究; 對腫瘤各個生長期的基因進行比較,以便找出微環境中抑制免疫反應的重要因子,將其應用在加強免疫治療的輔助上。初期研究結果如下,我們已成功來源骨髓來源 DC (BMDC),其來源效率為血液來源的 20 倍。BMDC 已與腫瘤細胞融合,初步製成 hybrid 疫苗,並證實此融合疫苗能有效抑制犬傳染性花柳病腫瘤。將以之作為其他腫瘤融合疫苗研發的評估。此外正利用 Affymatrix 尋找特異性抗原與防禦牆有關之基因。同時將利用過去本研究室發現與腫瘤微環境相關的 IL-6、IL-15 及 Calnexin 基因嘗試加入 DC 及腫瘤細胞的融合疫苗細胞內,藉以強化其抗原呈現功能。總結而言,本研究團隊目前致力於結合創新之免疫療法與基礎癌症細胞之基因研究,發展 DC 相關之癌症疫苗,提升動物體之免疫能力,並期望能有效對抗犬腫瘤之生長。
Abstract: Cancer is the number one cause of death in dogs. Most of the cancers are chemo-resistant due to the existence of the multi-drug resistance pump. Only small percentage of cancers is responsive to chemotherapeutic treatment. The toxicity of chemotherapeutic drugs further limits its clinical application. Moreover, tumor cells often escape host immune surveillance by more than one mechanism, such as low MHC expression, suppressive cytokines production and others. As the results, the immune cells come to be less efficient in the recognition of tumor-associated antigens and may develop into immune tolerance. Therefore, to activate immune activities especially the cytotoxic T lymhocytes has become an important research area in defending tumor growth. Comparing to traditional chemotherapy, immune therapy is more specific in killing tumor cells, thus, much less toxic. However there are still limitations for the immune therapy. One of the major reasons for the limitations is that the tumor cells usually evolve to establish a cytokine network and stroma shield, which are efficient in suppressing immune activities and avoiding possible attack from the host. Therefore, how to break this cancer defense mechanism and to recover the immune activities from the suppression have become important issues in cancer therapy. In this study, we first seek to enhance the tumor-suppressed dendritic cell functions by improving its antigen presenting ability. Second, we would study the mechanisms and genes that involve in the cancer immune evasion by comparing the gene expression levels in different growth stage of tumor and define the possible candidates, with which the host anti-cancer immune responses can be strengthened. In the preliminary results, we have successfully generated dendritic cells from bone marrow (BMDC) with a production efficient about 20 times more than that for the generation of the dendritic cells of blood origin. We have also fused the BMDC with canine transmissible venereal tumor and demonstrated its clinical potentials in the experimental canine model. In order to enhance the anti-tumor activities of the fusion hybrid vaccines, by applying our previous results associated with the understanding on cancer immune evasion, we will modify the fusion hybrids by transferring the IL-6, IL-15 or calnexin genes into the hybrids. In conclusion, our team is now focusing on combining the modified fusion hybrids with gene therapy and developing potent DC vaccines in treating canine cancers.
Keyword(s)
樹突狀細胞
犬傳染性花柳病腫瘤
融合型疫苗
IL-6/IL-15/Calnexin
Bone marrow derived dendritic cell / CTVT / fusion hybrids / IL-6
IL-15,