Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion.
Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion.
复制标题
DOI：
10.1073/pnas.2000915118
复制
发表时间：
2021-03-09
影响因子：
11.1
通讯作者：
Marchetti C
中科院分区：
文献类型：
--
作者：
Tengesdal IW;Menon DR;Osborne DG;Neff CP;Powers NE;Gamboni F;Mauro AG;D'Alessandro A;Stefanoni D;Henen MA;Mills TS;De Graaf DM;Azam T;Vogeli B;Palmer BE;Pietras EM;DeGregori J;Tan AC;Joosten LAB;Fujita M;Dinarello CA;Marchetti C
核苷酸结合结构域，富含亮氨酸的家族，pyrin结构域-3 （NLRP3）炎性体，一种调节白细胞介素(IL)-1β成熟和释放的细胞内复合物，在转移性黑色素瘤的活检中是活跃的。在这里，我们证明了NLRP3在黑色素瘤细胞中的激活驱动了小鼠肿瘤的进展。在黑色素瘤细胞中NLRP3激活后，IL-1β诱导黑色素瘤相关炎症，导致免疫抑制。口服单一NLRP3抑制剂（OLT1177）可减少黑色素瘤生长和黑色素瘤相关的髓源性抑制细胞扩增。与单药治疗相比，NLRP3信号的抑制与抗pd -1联合显示出增强的疗效。这些数据表明NLRP3是人类黑色素瘤的治疗靶点。白细胞介素-1β (IL-1β)介导的炎症抑制抗肿瘤免疫，导致肿瘤允许环境的产生，肿瘤生长和进展。在这里，我们证明了黑色素瘤中核苷酸结合结构域、富含亮氨酸的家族、pyrin结构域-3 （NLRP3）炎症小体的激活与IL-1β的产生、炎症和免疫抑制有关。肿瘤基因组数据集（TCGA和GTEx）分析显示，与正常皮肤（n = 324）相比，皮肤黑色素瘤样本（n = 469）中NLRP3和IL-1β的表达更高，NLRP3和IL-1β之间具有高度显著的相关性（P < 0.0001）。我们使用荧光共振能量转移分析NLRP3和含有CARD的凋亡相关斑点样蛋白，在转移性黑色素瘤活检中显示NLRP3炎性体的形成。在体内，肿瘤相关的NLRP3/IL-1信号传导诱导髓源性抑制细胞（MDSCs）的扩增，导致自然杀伤细胞和CD8+ T细胞活性降低，同时原发性肿瘤中调节性T细胞（Treg）的存在增加。dapansutrile （OLT1177）对肿瘤源性NLRP3的遗传或药理学抑制都足以减少MDSCs的扩增并增强抗肿瘤免疫，从而降低肿瘤生长。此外，我们观察到NLRP3抑制和抗pd -1治疗的联合通过限制mdsc介导的T细胞抑制和肿瘤进展，显着提高了单药治疗的抗肿瘤疗效。这些数据表明，NLRP3在黑色素瘤细胞中的激活是一种诱导MDSCs扩增和免疫逃逸的原瘤机制。我们得出结论，抑制NLRP3可以增强抗pd -1治疗的疗效。
The nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome, an intracellular complex that regulates maturation and release of interleukin (IL)-1β, is active in biopsies of metastatic melanoma. Here, we demonstrate that NLRP3 activation in melanoma cells drives tumor progression in mice. Subsequent to NLRP3 activation in melanoma cells, IL-1β induces melanoma-associated inflammation, resulting in immunosuppression. Oral administration of a single NLRP3 inhibitor (OLT1177) reduces melanoma growth and melanoma-associated myeloid-derived suppressor cell expansion. Inhibition of the NLRP3 signaling in combination with anti–PD-1 revealed augmented efficacy compared to monotherapy. These data propose that NLRP3 is a therapeutic target for human melanoma. Interleukin-1β (IL-1β)–mediated inflammation suppresses antitumor immunity, leading to the generation of a tumor-permissive environment, tumor growth, and progression. Here, we demonstrate that nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1β production, inflammation, and immunosuppression. Analysis of cancer genome datasets (TCGA and GTEx) revealed greater NLRP3 and IL-1β expression in cutaneous melanoma samples (n = 469) compared to normal skin (n = 324), with a highly significant correlation between NLRP3 and IL-1β (P < 0.0001). We show the formation of the NLRP3 inflammasome in biopsies of metastatic melanoma using fluorescent resonance energy transfer analysis for NLRP3 and apoptosis-associated speck-like protein containing a CARD. In vivo, tumor-associated NLRP3/IL-1 signaling induced expansion of myeloid-derived suppressor cells (MDSCs), leading to reduced natural killer and CD8+ T cell activity concomitant with an increased presence of regulatory T (Treg) cells in the primary tumors. Either genetic or pharmacological inhibition of tumor-derived NLRP3 by dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth. Additionally, we observed that the combination of NLRP3 inhibition and anti–PD-1 treatment significantly increased the antitumor efficacy of the monotherapy by limiting MDSC-mediated T cell suppression and tumor progression. These data show that NLRP3 activation in melanoma cells is a protumor mechanism, which induces MDSCs expansion and immune evasion. We conclude that inhibition of NLRP3 can augment the efficacy of anti–PD-1 therapy.
登录
查看更多内容
影响因子：
4.6
作者：
Guo B;Fu S;Zhang J;Liu B;Li Z
通讯作者：
Li Z
DOI：
10.1073/pnas.0611496104
发表时间：
2007-05-08
影响因子：
11.1
作者：
Duncan, Joseph A.;Bergstralht, Daniel T.;Ting, Jenny Pan-Yun
通讯作者：
Ting, Jenny Pan-Yun
DOI：
10.1073/pnas.1716095115
发表时间：
2018-02-13
影响因子：
11.1
作者：
Marchetti C;Swartzwelter B;Gamboni F;Neff CP;Richter K;Azam T;Carta S;Tengesdal I;Nemkov T;D'Alessandro A;Henry C;Jones GS;Goodrich SA;St Laurent JP;Jones TM;Scribner CL;Barrow RB;Altman RD;Skouras DB;Gattorno M;Grau V;Janciauskiene S;Rubartelli A;Joosten LAB;Dinarello CA
通讯作者：
Dinarello CA
影响因子：
5.8
作者：
Jordan, Kimberly R.;Amaria, Rodabe N.;Ramirez, Oscar;Callihan, Eryn B.;Gao, Dexiang;Borakove, Michelle;Manthey, Elizabeth;Borges, Virginia F.;McCarter, Martin D.
通讯作者：
McCarter, Martin D.
影响因子：
9.2
作者：
Dinarello, Charles A.
通讯作者：
Dinarello, Charles A.