[奇譽 光田： 劉耿僚 廖倩茹] 2013年3月1日最新的醫學研究期刊Jounral of Clinical Investigation發表： ”研究發現在惡性黑色素瘤中，IgG4抗體會削弱抗腫瘤免疫反應“ 人體宿主誘導產生的抗體和其對抗癌症與發炎過程所作出的貢獻，仍是尚待研究了解的醫學領域。在某些發炎狀況下，IgG4亞抗體存在於以IL-10驅動的Th2免疫反應當中。由於在體內癌症的微環境中，Th2型失控的炎症控制反應是腫瘤的一個明顯標誌，所以我們研究IgG4在惡性黑色素瘤的存在和對免疫功能的影響。與Th2細胞炎症反應性質一致，CD22+ B細胞和IgG4+浸潤細胞會在腫瘤中累積，和IL-10，IL-4，和腫瘤反應性的IgG4在腫瘤原位過度產生。相對於患者的原始的淋巴結和血液的B細胞，在腫瘤中的B細胞會極化產生過量的IgG4。腫瘤中的分泌型B細胞會增加VEGF和IgG4的產生，和腫瘤細胞增強IL-10的分泌一樣。不同於IgG1，一個基因工程設計的細胞外實驗顯示，腫瘤抗原特異性IgG4對殺死腫瘤並沒有效果。抗原特異性和非特異性IgG4則會抑制IgG1殺腫瘤的功能。 此外，血清中IgG4濃度與癌症患者的生存率呈負相關，也就是IgG4濃度越高，病人存活期越短。這些研究結果表明，IgG4會促進了腫瘤誘導的Th2錯誤抗發炎效應，進而可能會限制了其它免疫系統對抗腫瘤細胞的免疫功能，誘導腫瘤對免疫系統的逃逸能力，這個發現提供了可能進一步的針對腫瘤生物標誌物的發展，和個別癌症病人可能需要特異治療方式的研究方向。 ----------------------------------------------------------------------------------------- J Clin Invest. 2013 Mar 1. IgG4 subclass antibodies impair antitumor immunity in melanoma. Karagiannis P, Gilbert AE, Josephs DH, Ali N, Dodev T, Saul L, Correa I, Roberts L, Beddowes E, Koers A, Hobbs C, Ferreira S, Geh JL, Healy C, Harries M, Acland KM, Blower PJ, Mitchell T, Fear DJ, Spicer JF, Lacy KE, Nestle FO, Karagiannis SN. Abstract Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10-driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22+ B cells and IgG4+-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell-mediated tumor killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of FcγRI activation. Additionally, IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches.
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