Combination of STING and TLR 7/8 Agonists as Vaccine Adjuvants for Cancer Immunotherapy.
Combination of STING and TLR 7/8 Agonists as Vaccine Adjuvants for Cancer Immunotherapy.
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免疫佐剂的临床应用受到短暂反应和各种副作用的限制。本研究调查了组合TLR 7/8激动剂（522）和STING激动剂（DMXAA）以产生稳健的抗癌免疫应答的多佐剂方法。卵白蛋白+DMXAA+522免疫可激活淋巴结、脾脏和肿瘤中的DC。该组合还引起比对照或单独治疗更强的抗原特异性CD 8 + T细胞和NK细胞应答。与其他对照相比，用OVA+DMXAA+522免疫导致显著的肿瘤生长抑制和改善的存活。有效激活抗原呈递细胞并（反过来）引发细胞毒性T细胞的免疫刺激佐剂是抗癌疫苗的关键组分。在这项研究中，我们研究了一种结合TLR 7/8激动剂（522）和STING激动剂（DMXAA）的多佐剂方法，以促进增强的抗原交叉呈递，刺激特异性抗肿瘤T细胞应答，并提供改善的抗癌功效。使用骨髓来源的树突状细胞（BMDC）进行的体外实验证实，基于共刺激分子表达和促炎细胞因子分泌，522-DMXAA组合增强了激活。相对于单激动剂疫苗，用包含522和DMXAA两者的疫苗免疫小鼠在B16 F10黑素瘤和MB 49膀胱肿瘤模型中产生更大的抗肿瘤功效。免疫小鼠免疫细胞的基于流式细胞术的分析揭示了抗原呈递细胞的显著活化，脾和淋巴结中活化和Ag特异性CD 8 + T细胞的数量增加，NK细胞的适度活化，以及CD 206+巨噬细胞的总体减少。这些结果得到了血清中IFN-γ水平升高和IL-10水平降低的支持。总之，这些发现证明了TLR 7/8和STING激动剂组合作为疫苗佐剂激活先天性和适应性免疫应答的潜力。
The clinical use of immunoadjuvants is limited by transient responses and various side effects. This study investigated the multi-adjuvant approach of combining a TLR 7/8 agonist (522) and a STING agonist (DMXAA) to generate a robust anticancer immune response. Immunization with ovalbumin+DMXAA+522 resulted in the activation of DCs in lymph nodes, spleen, and tumor. The combination also elicited stronger antigen-specific CD8+ T cell and NK cell responses than the control or individual treatments. Immunization with OVA+DMXAA+522 resulted in significant tumor growth inhibition and improved survival compared to other controls. Immunostimulatory adjuvants that potently activate antigen-presenting cells and (in turn) prime cytotoxic T cells are a key component of anticancer vaccines. In this study, we investigated a multi-adjuvant approach combining a TLR 7/8 agonist (522) and a STING agonist (DMXAA) to promote enhanced antigen cross-presentation, stimulate specific antitumor T-cell responses, and provide improved anticancer efficacy. In vitro experiments using bone marrow-derived dendritic cells (BMDCs) confirmed enhanced activation with the 522-DMXAA combination based on both co-stimulatory molecule expression and pro-inflammatory cytokine secretion. The immunization of mice with vaccines comprising both 522 and DMXAA resulted in greater antitumor efficacy in B16F10 melanoma and MB49 bladder tumor models relative to mono-agonist vaccines. Flow cytometry-based analysis of immune cells from immunized mice revealed the significant activation of antigen-presenting cells, increased numbers of activated and Ag-specific CD8+ T cells in the spleen and lymph nodes, modest NK cell activation, and an overall reduction in CD206+ macrophages. These results were supported by an increase in the levels of IFN-γ and a reduction in IL-10 levels in the sera. Taken together, these findings demonstrate the potential of the TLR7/8 and STING agonist combination as vaccine adjuvants to activate both innate and adaptive immune responses.
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影响因子：
8.8
作者：
Fridlender ZG;Jassar A;Mishalian I;Wang LC;Kapoor V;Cheng G;Sun J;Singhal S;Levy L;Albelda SM
通讯作者：
Albelda SM
影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1016/s0360-3016(02)03920-2
发表时间：
2002-12-01
影响因子：
7
作者：
Baguley, BC;Ching, LM
通讯作者：
Ching, LM
DOI：
10.4049/jimmunol.1701492
发表时间：
2018-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Brault M;Olsen TM;Martinez J;Stetson DB;Oberst A
通讯作者：
Oberst A
影响因子：
4.4
作者：
Deb, Pratik;Dai, Jihong;Fitzgerald-Bocarsly, Patricia
通讯作者：
Fitzgerald-Bocarsly, Patricia