A Potential Herbal Adjuvant Combined With a Peptide-Based Vaccine Acts Against HPV-Related Tumors Through Enhancing Effector and Memory T-Cell Immune Responses
摘要
人類乳突病毒(HPV)的感染可能跟許多癌症的發生有關，尤其，大約70%的子宮頸癌與HPV 16與18型的感染有關。一些研究已證明在腫瘤周圍的慢性發炎及免疫抑制細胞的存在與HPV誘導癌症的發生有關。雖然已經有兩種預防型的HPV疫苗產品來避免HPV的感染，然而仍然需要針對HPV誘發的癌症，來發展出治療型的 HPV疫苗。至今，對於針對HPV誘導癌症的免疫療法的不同策略方向，都還正在研究發展中。
在中國，傳統中藥已經是很重要用來治療癌症病人的策略。一些傳統中藥的萃取物已經證實其作用類似類繹受體(TLR)，並且應用於不同疫苗的佐劑來誘導樹突細胞(DC)的活化、細胞激素的活化以及細胞/體液免疫的反應。更進一步，一些研究已經證實傳統中藥可以調控腫瘤周圍環境PD-1及PD-L1的產生、細胞激素的表現以及免疫抑制細胞的增生。因此，中草藥增加抗腫瘤免疫反應的機制可能是經由減少免疫抑制細胞及增加專一性T細胞的反應。然而這些機制尚需研究證實。
我的研究表明，利用國家健康保險研究數據庫 (NHIRD) 的分析顯示，白花蛇舌草是子宮頸癌等癌症患者常用的單味藥。此外，我們證明了白花蛇舌草萃取物通過MAPK訊息傳遞路徑誘導老鼠和人的抗原呈現細胞 (APC) 活化，並在體外樹突細胞 (BMDC) 中的抗原呈遞能力。此外，我們發現用白花蛇舌草治療會增強體內特異性效應和記憶 T 細胞的反應。在預防、治療和復發性 HPV 相關腫瘤模型中，使用胜肽疫苗與白花蛇舌草萃取物的結合治療，可提高抗腫瘤活性。此外，我們發現蘆丁是白花蛇舌草萃取物中的一種成分，可在體內誘導針對 HPV 相關腫瘤的強烈特異性免疫反應。總之，我們證明了白花蛇舌草萃取物及其活性化合物蘆丁可用作胜肽疫苗中的佐劑，以增加免疫原性並取代傳統佐劑。此外，免疫刺激型的中藥萃取物與癌症疫苗的結合可能會在治療病毒誘導的癌症的新策略中取得進展。
Abstract
Human papillomavirus (HPV) infections may account for the development of several cancers; in particular, HPV16 and HPV18 are known to cause around 70% of cervical cancer cases. Some studies have demonstrated that chronic inflammation and immune suppressive cells in tumor microenvironment are associated in the development of HPV-induced cancer. Even though there are two preventive HPV vaccines (Cervarix® and Gardasil®) used to avoid HPV infection, the development of efficient therapeutic vaccine for HPV-related cancer is still needed. Until now, several approaches for immunotherapy of HPV-induced cancer are under development.
Traditional Chinese herbal medicine (CHM) has been a very important complementary strategy for treating cancer in china. CHM extracts have been demonstrated that could act as TLR agonists and use as adjuvant to induce DC activation, cytokine production and cellular/humoral immune responses in different vaccine strategy. Further, some studies have found that CHMs could modulate PD-1/PD-L1 production, cytokines expression and immunosuppressive population in tumor microenvironment. Therefore, the mechanism of CHM on enhancing antitumor immune responses may be via modulating specific T cells and/or immunosuppressive populations. However, these mechanisms remain to be clarified.
My study demonstrated that Hedyotis diffusa Willd (BHSSC) was the commonly used single herbs in cancer patients such as cervical cancer, which are analyzed the prescription patterns in the National Health Insurance Research Database (NHIRD). Furthermore, we demonstrated that BHSSC induces murine and human antigen-presenting cell (APC) activation via the MAPK signaling pathway and enhances antigen presentation in bone marrow-derived dendritic cells (BMDCs) in vitro. Furthermore, we identified that treatment with BHSSC leads to improved specific effector and memory T-cell responses in vivo. Variant peptide-based vaccines combined with BHSSC improved antitumor activity in preventive, therapeutic, and recurrent HPV-related tumor models. Furthermore, we showed that rutin, one of the ingredients in BHSSC, induces a strong specific immune response against HPV-related tumors in vivo. In summary, we demonstrated that BHSSC extract and its active compound, rutin, can be used as adjuvants in peptide-based vaccines to increase immunogenicity and to bypass the requirement of a conditional adjuvant. Further, immune-stimulator CHM combined with cancer vaccine may be progressed in novel strategies to treat virus-induced cancers.