Using macrophage activation to augment immunotherapy of established tumours.
Using macrophage activation to augment immunotherapy of established tumours.
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DOI：
10.1038/bjc.2013.93
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发表时间：
2013-04-02
影响因子：
8.8
通讯作者：
Albelda SM
中科院分区：
文献类型：
--
作者：
Fridlender ZG;Jassar A;Mishalian I;Wang LC;Kapoor V;Cheng G;Sun J;Singhal S;Levy L;Albelda SM
成功的免疫治疗需要改变肿瘤微环境和/或减少免疫抑制。肿瘤相关巨噬细胞（TAM）是影响肿瘤微环境的主要因素之一。我们假设改变TAM表型将增强免疫治疗的功效。我们和其他人已经报道了5，6-二甲基氧杂蒽酮-4-乙酸（DMXAA，Vadimezan）具有改变TAM表型的能力，诱导有利于抗肿瘤免疫应答的肿瘤微环境。因此，我们将DMXAA与主动免疫疗法相结合，并评估了抗肿瘤疗效，免疫细胞表型（流式细胞术）和肿瘤微环境（RT-PCR）。在几种不同的肺癌免疫治疗小鼠模型中，DMXAA诱导的巨噬细胞活化显著增强了免疫治疗的治疗效果。通过增加中性粒细胞和抗肿瘤（M1）巨噬细胞流入肿瘤，DMXAA改变了骨髓细胞表型，从而改变了肿瘤内M2/非M2 TAM免疫抑制比。它还改变了肿瘤微环境，使其更具促炎性。在免疫治疗期间调节巨噬细胞导致肿瘤内CD 8 + T细胞的数量、活性和抗原特异性增加。巨噬细胞耗竭降低了免疫疗法与巨噬细胞活化的组合作用，支持TAM在组合作用中的重要性。调节肿瘤内巨噬细胞显著增强了免疫治疗的效果。我们的观察结果表明，在未来的试验中应考虑在免疫治疗中加入激活TAM的药物。
Successful immunotherapy will require alteration of the tumour microenvironment and/or decreased immune suppression. Tumour-associated macrophages (TAMs) are one major factor affecting tumour microenvironment. We hypothesised that altering TAM phenotype would augment the efficacy of immunotherapy. We and others have reported that 5,6-Dimethylxanthenone-4-acetic-acid (DMXAA, Vadimezan) has the ability to change TAM phenotypes, inducing a tumour microenvironment conducive to antitumour immune responses. We therefore combined DMXAA with active immunotherapies, and evaluated anti-tumour efficacy, immune cell phenotypes (flow cytometry), and tumour microenvironment (RT–PCR). In several different murine models of immunotherapy for lung cancer, DMXAA-induced macrophage activation significantly augmented the therapeutic effects of immunotherapy. By increasing influx of neutrophils and anti-tumour (M1) macrophages to the tumour, DMXAA altered myeloid cell phenotypes, thus changing the intratumoural M2/non-M2 TAM immunoinhibitory ratio. It also altered the tumour microenvironment to be more pro-inflammatory. Modulating macrophages during immunotherapy resulted in increased numbers, activity, and antigen-specificity of intratumoural CD8+ T cells. Macrophage depletion reduced the effect of combining immunotherapy with macrophage activation, supporting the importance of TAMs in the combined effect. Modulating intratumoural macrophages dramatically augmented the effect of immunotherapy. Our observations suggest that addition of agents that activate TAMs to immunotherapy should be considered in future trials.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
11.2
作者：
Fridlender ZG;Buchlis G;Kapoor V;Cheng G;Sun J;Singhal S;Crisanti MC;Wang LC;Heitjan D;Snyder LA;Albelda SM
通讯作者：
Albelda SM
影响因子：
11.2
作者：
Kim S;Buchlis G;Fridlender ZG;Sun J;Kapoor V;Cheng G;Haas A;Cheung HK;Zhang X;Corbley M;Kaiser LR;Ling L;Albelda SM
通讯作者：
Albelda SM
影响因子：
11.2
作者：
Aharinejad, S;Paulus, P;Abraham, D
通讯作者：
Abraham, D
影响因子：
6.1
作者：
Baguley BC;Siemann DW
通讯作者：
Siemann DW