AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma.
AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma.
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DOI：
10.1084/jem.20200962
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发表时间：
2021-09-06
期刊：
影响因子：
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通讯作者：
Harris JE
中科院分区：
文献类型：
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作者：
Fukuda K;Okamura K;Riding RL;Fan X;Afshari K;Haddadi NS;McCauley SM;Guney MH;Luban J;Funakoshi T;Yaguchi T;Kawakami Y;Khvorova A;Fitzgerald KA;Harris JE
Fukuda等人证明，人黑素瘤内DC中的AIM 2表达是预后不良的标志，并且AIM 2缺陷型DC疫苗接种通过促进STING诱导的IFN分泌以及限制IL-1β和IL-18产生来增强黑素瘤免疫应答。STING和黑素瘤2（AIM 2）中缺失的途径通过胞质DNA的存在而被激活，并且STING激动剂增强免疫应答。在这里，我们表明，树突状细胞（DC）表达的AIM 2在人黑色素瘤与预后不良，相比，STING，AIM 2发挥免疫抑制作用的黑色素瘤微环境。用AIM 2缺陷型DC进行疫苗接种提高了过继性T细胞疗法和抗PD-1免疫疗法对表现出不良治疗应答的“冷肿瘤”的功效。这种效应不依赖于接种疫苗的DC的延长存活，而是依赖于肿瘤来源的DNA，其激活STING依赖性I型IFN分泌和随后的CXCL 10产生以募集CD 8 + T细胞。此外，AIM 2依赖性IL-1β和IL-18加工的丧失通过限制调节性T细胞的募集进一步增强了治疗应答。最后，AIM 2 siRNA处理的小鼠DCs在体内和人DCs在体外增强了类似的抗肿瘤免疫应答。因此，靶向肿瘤浸润性DC中的AIM 2是黑色素瘤的有希望的新治疗策略。
Fukuda et al. demonstrate that AIM2 expression in DCs within human melanoma is a poor prognostic sign and that AIM2-deficient DC vaccination enhances melanoma immunotherapeutic responses by promoting STING-induced IFN secretion as well as limiting IL-1β and IL-18 production. The STING and absent in melanoma 2 (AIM2) pathways are activated by the presence of cytosolic DNA, and STING agonists enhance immunotherapeutic responses. Here, we show that dendritic cell (DC) expression of AIM2 within human melanoma correlates with poor prognosis and, in contrast to STING, AIM2 exerts an immunosuppressive effect within the melanoma microenvironment. Vaccination with AIM2-deficient DCs improves the efficacy of both adoptive T cell therapy and anti–PD-1 immunotherapy for “cold tumors,” which exhibit poor therapeutic responses. This effect did not depend on prolonged survival of vaccinated DCs, but on tumor-derived DNA that activates STING-dependent type I IFN secretion and subsequent production of CXCL10 to recruit CD8+ T cells. Additionally, loss of AIM2-dependent IL-1β and IL-18 processing enhanced the treatment response further by limiting the recruitment of regulatory T cells. Finally, AIM2 siRNA-treated mouse DCs in vivo and human DCs in vitro enhanced similar anti-tumor immune responses. Thus, targeting AIM2 in tumor-infiltrating DCs is a promising new treatment strategy for melanoma.