STING Activation Reverses Lymphoma-Mediated Resistance to Antibody Immunotherapy.
STING Activation Reverses Lymphoma-Mediated Resistance to Antibody Immunotherapy.
复制标题
DOI：
10.1158/0008-5472.can-16-2784
复制
发表时间：
2017-07-01
期刊：
影响因子：
11.2
通讯作者：
Beers SA
中科院分区：
文献类型：
--
作者：
Dahal LN;Dou L;Hussain K;Liu R;Earley A;Cox KL;Murinello S;Tracy I;Forconi F;Steele AJ;Duriez PJ;Gomez-Nicola D;Teeling JL;Glennie MJ;Cragg MS;Beers SA
肿瘤通常会吸引和吸收巨噬细胞，以促进其生长、血管生成和转移。巨噬细胞也是单克隆抗体（mAb）疗法的关键效应细胞。在此，我们报告了肿瘤微环境在肿瘤相关巨噬细胞（TAM）上产生了免疫抑制特征，该特征有利于抑制性而非活化性Fcγ受体（FcγR）的表达，从而限制了mAb免疫治疗的疗效。我们评估了一组TLR和STING激动剂（a）将巨噬细胞重编程至mAb免疫疗法的最佳状态的能力。STINGa和TLRa均诱导细胞因子释放，调节FcγR表达并增强mAb介导的肿瘤细胞吞噬作用。然而，只有STINGa在体内逆转了抑制性FcγR谱，在淋巴瘤小鼠模型中为抗CD20 mAb提供了强佐剂效应。有效的佐剂如STINGa可以改善TAM上的FcγR活化：抑制（A：I）比率，是重新编程TAM和抑制肿瘤介导的免疫抑制的有吸引力的候选物，从而增强mAb功效。
Tumors routinely attract and co-opt macrophages to promote their growth, angiogenesis and metastasis. Macrophages are also the key effector cell for monoclonal antibody (mAb) therapies. Here we report that the tumor microenvironment creates an immunosuppressive signature on tumor-associated macrophages (TAM) which favors expression of inhibitory rather than activating Fcγ receptors (FcγR), thereby limiting the efficacy of mAb immunotherapy. We assessed a panel of TLR and STING agonists (a) for their ability to reprogram macrophages to a state optimal for mAb immunotherapy. Both STINGa and TLRa induced cytokine release, modulated FcγR expression and augmented mAb-mediated tumor cell phagocytosis in vitro. However, only STINGa reversed the suppressive FcγR profile in vivo, providing strong adjuvant effects to anti-CD20 mAb in murine models of lymphoma. Potent adjuvants like STINGa which can improve FcγR activatory:inhibitory (A:I) ratios on TAM are appealing candidates to reprogram TAM and curb tumor-mediated immunosuppression, thereby empowering mAb efficacy.