STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation.
STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation.
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DOI：
10.1136/jitc-2021-002852
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发表时间：
2021-07
影响因子：
10.9
通讯作者：
Harashima H
中科院分区：
文献类型：
--
作者：
Nakamura T;Sato T;Endo R;Sasaki S;Takahashi N;Sato Y;Hyodo M;Hayakawa Y;Harashima H
对免疫检查点抑制剂（ICI）的耐药性是癌症免疫治疗的主要障碍。ICI抗性的原因包括主要组织相容性复合体（MHC）/组织相容性位点抗原（HLA）I类丢失、新抗原丢失和不完全抗原呈递。自然杀伤（NK）细胞的消除有望成为治疗这些ICI耐药肿瘤的有效策略。我们先前证明了含有干扰素基因（STING）激动剂（STING-LNP）刺激剂的脂质纳米颗粒通过激活NK细胞有效诱导抗肿瘤活性。因此，我们评估了STING-LNP降低ICI抗性的潜力。使用B16-F10小鼠黑素瘤的肺转移作为抗程序性细胞死亡1（抗PD-1）抗性小鼠模型。将小鼠静脉内注射STING-LNP，并通过RT-qPCR和流式细胞术分析负责STING-LNP改善抗PD-1抗性的机制。还研究了STING-LNP的动力学。尽管抗PD-1单一疗法未能诱导抗肿瘤作用，但STING-LNP和抗PD-1的组合发挥协同抗肿瘤作用。我们的结果表明，STING-LNP治疗显著增加了肺转移瘤中CD 3、CD 4、NK 1.1、PD-1和干扰素（IFN）-γ的表达。这种变化似乎是由含有内化的STING-LNP的肝巨噬细胞产生的I型IFN引发的，导致表达PD-1的NK细胞的全身活化。活化的NK细胞似乎产生IFN-γ，导致癌细胞中PD配体1（PD-L1）的表达增加，从而在施用抗PD-1时产生协同抗肿瘤作用。我们提供了证明STING-LNP治疗可以克服B16-F10肺转移模型中的PD-1抗性的证明。对此负责的机制表明，NK细胞通过刺激STING途径被激活，STING途径反过来诱导癌细胞上PD-L1的表达。基于本文报道的发现，STING-LNP代表了用于与抗PD-1耐药肿瘤联合治疗的有希望的候选物。
Resistance to an immune checkpoint inhibitor (ICI) is a major obstacle in cancer immunotherapy. The causes of ICI resistance include major histocompatibility complex (MHC)/histocompatibility locus antigen (HLA) class I loss, neoantigen loss, and incomplete antigen presentation. Elimination by natural killer (NK) cells would be expected to be an effective strategy for the treatment of these ICI-resistant tumors. We previously demonstrated that a lipid nanoparticle containing a stimulator of an interferon gene (STING) agonist (STING-LNP) efficiently induced antitumor activity via the activation of NK cells. Thus, we evaluated the potential of reducing ICI resistance by STING-LNPs. Lung metastasis of a B16-F10 mouse melanoma was used as an anti-programmed cell death 1 (anti-PD-1)-resistant mouse model. The mice were intravenously injected with the STING-LNP and the mechanism responsible for the improvement of anti-PD-1 resistance by the STING-LNPs was analyzed by RT-qPCR and flow cytometry. The dynamics of STING-LNP were also investigated. Although anti-PD-1 monotherapy failed to induce an antitumor effect, the combination of the STING-LNP and anti-PD-1 exerted a synergistic antitumor effect. Our results indicate that the STING-LNP treatment significantly increased the expression of CD3, CD4, NK1.1, PD-1 and interferon (IFN)-γ in lung metastases. This change appears to be initiated by the type I IFN produced by liver macrophages that contain the internalized STING-LNPs, leading to the systemic activation of NK cells that express PD-1. The activated NK cells appeared to produce IFN-γ, resulting in an increase in the expression of the PD ligand 1 (PD-L1) in cancer cells, thus leading to a synergistic antitumor effect when anti-PD-1 is administered. We provide a demonstration to show that a STING-LNP treatment can overcome PD-1 resistance in a B16-F10 lung metastasis model. The mechanism responsible for this indicates that NK cells are activated by stimulating the STING pathway which, in turn, induced the expression of PD-L1 on cancer cells. Based on the findings reported herein, the STING-LNP represents a promising candidate for use in combination therapy with anti-PD-1-resistant tumors.
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DOI：
10.1084/jem.20101159
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fuertes MB;Kacha AK;Kline J;Woo SR;Kranz DM;Murphy KM;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1084/jem.20160801
发表时间：
2017-04-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Juneja VR;McGuire KA;Manguso RT;LaFleur MW;Collins N;Haining WN;Freeman GJ;Sharpe AH
通讯作者：
Sharpe AH
影响因子：
64.8
作者：
De Henau O;Rausch M;Winkler D;Campesato LF;Liu C;Cymerman DH;Budhu S;Ghosh A;Pink M;Tchaicha J;Douglas M;Tibbitts T;Sharma S;Proctor J;Kosmider N;White K;Stern H;Soglia J;Adams J;Palombella VJ;McGovern K;Kutok JL;Wolchok JD;Merghoub T
通讯作者：
Merghoub T
影响因子：
7.3
作者：
Lioux, Thierry;Mauny, Marc-Antoine;Tiraby, Gerard
通讯作者：
Tiraby, Gerard
影响因子：
17.4
作者：
Gustafson HH;Holt-Casper D;Grainger DW;Ghandehari H
通讯作者：
Ghandehari H