The Alarmin HMGN1 contributes to antitumor immunity and is a potent immunoadjuvant.
The Alarmin HMGN1 contributes to antitumor immunity and is a potent immunoadjuvant.
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DOI：
10.1158/0008-5472.can-13-2042
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发表时间：
2014-11-01
期刊：
影响因子：
11.2
通讯作者：
Oppenheim JJ
中科院分区：
文献类型：
--
作者：
Wei F;Yang D;Tewary P;Li Y;Li S;Chen X;Howard OM;Bustin M;Oppenheim JJ
Alarmins是内源性介质，其响应于危险信号而被迅速引发，通过促进抗原呈递细胞（APC）的募集和成熟来增强先天性和适应性免疫应答。核小体结合蛋白HMGN 1是一种有效的alarmin，其结合TLR 4并诱导抗原特异性Th 1免疫应答，但其对抗肿瘤免疫的贡献尚未被探索。我们发现，表达卵清蛋白（OVA）的EG 7小鼠胸腺瘤细胞在Hmgn 1缺陷小鼠中的生长速度比同窝对照组快得多。荷瘤Hmgn 1 −/−小鼠在脾脏中产生的OVA特异性CD 8细胞比荷EG 7 Hmgn 1 +/+小鼠少，表明Hmgn 1支持T细胞介导的抗肿瘤免疫。此外，表达HMGN 1的EG 7肿瘤比对照EG 7肿瘤生长更慢，表明对表达HMGN 1的肿瘤具有更大的抗性。这种抗性依赖于T细胞介导的免疫，因为它通过体内消耗CD 4+和CD 8 + T细胞而消除。此外，用表达HMGN 1-gp 100融合蛋白的DNA载体接种的小鼠表现出gp 100特异性、Th 1极化的免疫应答，获得对小鼠B16 F1黑素瘤攻击的抗性。总的来说，我们的研究结果表明，HMGN 1有助于抗肿瘤免疫，它可能提供一种有效的佐剂，以提高对癌症疫苗的反应。
Alarmins are endogenous mediators that are elicited rapidly in response to danger signals, enhancing innate and adaptive immune responses by promoting the recruitment and maturation of antigen-presenting cells (APCs). The nucleosome-binding protein HMGN1 is a potent alarmin that binds TLR4 and induces antigen-specific Th1 immune responses, but its contributions to antitumor immunity have not been explored. We found that ovalbumin (OVA)-expressing EG7 mouse thymoma cells grew much faster in Hmgn1-deficient mice than littermate-matched controls. Tumor-bearing Hmgn1−/− mice generated fewer OVA-specific CD8 cells in the spleen than EG7-bearing Hmgn1+/+ mice, suggesting that HMGN1 supported T cell-mediated antitumor immunity. Additionally, EG7 tumors expressing HMGN1grew more slowly than control EG7 tumors, suggesting greater resistance to HMGN1-expressing tumors. This resistance relied on T cell mediated immunity because it was abolished by in vivo depletion of CD4+ and CD8+ T cells. Moreover, Mice vaccinated with a DNA vector expressing an HMGN1-gp100 fusion protein manifested gp100-specific, Th1-polarized immune responses, acquiring resistance to challenge with mouse B16F1 melanoma. Overall, our findings show that HMGN1 contributes to antitumor immunity and it may offer an effective adjuvant to heighten responses to cancer vaccines.