研究細菌外膜囊泡的抗腫瘤作用

Abstract

「外膜囊泡」是革蘭氏陰性細菌的外膜自然釋放出的胞外囊泡。此一種奈米顆粒大小的外膜囊泡含有豐富多樣的病原相關分子模式，其中包括格蘭氏陰細菌特有的內毒素「脂多醣」。近年來，許多研究利用外膜囊泡能夠引發先天性和適應性免疫反應的特性，將其廣泛應用在癌症免疫療法之領域。然而，外膜囊泡中作為誘導免疫反應與抑制腫瘤生長的關鍵成分，目前仍需更多詳細研究。在本篇研究中，我們系統地研究了脂多醣免疫原性對外膜囊泡抗腫瘤作用的影響。在我們的研究結果中顯示，脂多醣免疫原性的變化並不會影響外膜囊泡誘導抗原呈現細胞成熟的能力。然而，脂多醣免疫原性對外膜囊泡的抗腫瘤效應有著關鍵作用，而其中可能的原因為影響其招募白血球浸潤到腫瘤之中的能力有關。為了進一步增強對抗腫瘤的免疫反應，我們將外膜囊泡療法與化療藥物奧沙利寶結合使用，預期利用奧沙利寶誘導癌細胞引發免疫原性細胞死亡，並且協同外膜囊泡療法達到增強對抗腫瘤之免疫反應。此外我們嘗試將不同的類鐸受體激動劑表達在外膜囊泡上，預期能進一步增加其引發免疫反應對抗癌症之能力，儘管此策略在本次研究中未能產生預期的效果，但此種成功改造外膜囊泡的方式，仍然保有許多研究發展的可能性。總結，本篇研究揭示了脂多醣之免疫原性對於外膜囊泡建立免疫系統對抗癌症功效的重要性。

Outer membrane vesicles (OMVs) are nano-meter-sized exosomes naturally derived from the outer membrane of Gram-negative bacteria. They contain diverse pathogen-associated molecular patterns (PAMPs), with a particular enrichment of lipopolysaccharides (LPS). Recently, OMV-based applications have gained wide interest as cancer immunotherapy since they have been reported to provoke innate and adaptive immunity against tumors. However, the key component of OMVs that induces cancer immunity still remains largely unknown. In this study, we systemically investigated the impact of LPS immunogenicity on the anti-tumor effects of OMVs. Our results showed that variations in LPS immunogenicity did not affect the ability of OMVs to induce the maturation of antigen-presenting cells (APCs). However, we observed that the immunogenicity of LPS played a crucial role in the anti-tumor effects of OMVs, possibly by influencing the recruitment of tumor-infiltrating leukocytes. To further enhance the immune response against tumors, we combined the OMV-based therapy with the chemotherapeutic drug oxaliplatin, an inducer of immunogenic cell death (ICD), to synergistically boost immunity against the tumor. Moreover, we explored the possibility of enhancing OMV-based immune therapy by engineering additional Toll-like receptor agonists onto OMVs. Although this approach did not yield the desired outcome, the potential of engineered OMV-based therapy with other therapeutic proteins still holds great promise and warrants further investigation. Together, our findings shed light on the role of LPS immunogenicity in the recruitment of tumor-infiltrating leukocytes and its impact on the anti-tumor effects of OMVs. These insights contribute to a better understanding of OMVs as potential immunotherapeutic agents.