Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti-PD-1 immunotherapy.
Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti-PD-1 immunotherapy.
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DOI：
10.1126/scitranslmed.abq7019
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发表时间：
2022-11-23
影响因子：
17.1
通讯作者：
Hanks BA
中科院分区：
文献类型：
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作者：
Theivanthiran B;Yarla N;Haykal T;Nguyen YV;Cao L;Ferreira M;Holtzhausen A;Al-Rohil R;Salama AKS;Beasley GM;Plebanek MP;DeVito NC;Hanks BA
肿瘤固有的NOD-， LRR-和pyrin结构域蛋白-3 （NLRP3）炎症小体-热休克蛋白70 （HSP70）信号轴由CD8+ T细胞细胞毒性触发，并通过将粒细胞多形核髓源性抑制细胞（PMN MDSCs）募集到肿瘤微环境中，促进抗程序性细胞死亡蛋白1 （PD-1）免疫治疗的适应性抗性发展。在这里，我们证明肿瘤NLRP3-HSP70轴也以依赖于肺上皮细胞toll样受体4 （TLR4）信号传导的方式驱动PMN-MDSCs向远处肺组织的积累，建立一个转移前生态位，支持疾病对抗pd -1免疫治疗的超进展。肺上皮HSP70-TLR4信号通路诱导下游wnt5a依赖性粒细胞集落刺激因子（G-CSF）和C-X-C基序趋化因子配体5 （CXCL5）的释放，从而促进髓系粒细胞生成和PMN-MDSCs向肺组织募集。抗pd -1免疫治疗通过免疫压力增强了该通路的激活，并在Nlrp3扩增的情况下驱动疾病进展。在临床前黑色素瘤和乳腺癌模型中，NLRP3和HSP70的遗传和药理学抑制可阻断PMN-MDSC在抗pd -1治疗下在肺中的积累，并抑制转移进展。在接受抗pd -1免疫治疗的IV期黑色素瘤患者中，血浆HSP70基线浓度升高和肿瘤组织标本中NLRP3信号活性的证据与疾病过度进展和低生存率的发展相关。总之，这项工作描述了黑色素瘤疾病超进展现象的致病机制，并提供了能够改善黑色素瘤患者管理的候选靶点和标记物。
The tumor-intrinsic NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome–heat shock protein 70 (HSP70) signaling axis is triggered by CD8+ T cell cytotoxicity and contributes to the development of adaptive resistance to anti–programmed cell death protein 1 (PD-1) immunotherapy by recruiting granulocytic polymorphonuclear myeloid derived suppressor cells (PMN MDSCs) into the tumor microenvironment. Here, we demonstrate that the tumor NLRP3-HSP70 axis also drives the accumulation of PMN-MDSCs into distant lung tissues in a manner that depends on lung epithelial cell Toll-like receptor 4 (TLR4) signaling, establishing a premetastatic niche that supports disease hyperprogression in response to anti–PD-1 immunotherapy. Lung epithelial HSP70-TLR4 signaling induces the downstream Wnt5a-dependent release of granulocyte colony-stimulating factor (G-CSF) and C-X-C motif chemokine ligand 5 (CXCL5), thus promoting myeloid granulopoiesis and recruitment of PMN-MDSCs into pulmonary tissues. Treatment with anti–PD-1 immunotherapy enhanced the activation of this pathway through immunologic pressure and drove disease progression in the setting of Nlrp3 amplification. Genetic and pharmacologic inhibition of NLRP3 and HSP70 blocked PMN-MDSC accumulation in the lung in response to anti–PD-1 therapy and suppressed metastatic progression in preclinical models of melanoma and breast cancer. Elevated baseline concentrations of plasma HSP70 and evidence of NLRP3 signaling activity in tumor tissue specimens correlated with the development of disease hyperprogression and inferior survival in patients with stage IV melanoma undergoing anti–PD-1 immunotherapy. Together, this work describes a pathogenic mechanism underlying the phenomenon of disease hyperprogression in melanoma and offers candidate targets and markers capable of improving the management of patients with melanoma.
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影响因子：
64.5
作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
通讯作者：
Minn AJ
DOI：
10.1158/1078-0432.ccr-16-3133
发表时间：
2017-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kato S;Goodman A;Walavalkar V;Barkauskas DA;Sharabi A;Kurzrock R
通讯作者：
Kurzrock R
影响因子：
10.1
作者：
Holtzhausen A;Zhao F;Evans KS;Tsutsui M;Orabona C;Tyler DS;Hanks BA
通讯作者：
Hanks BA
影响因子：
4.8
作者：
Kumawat, Kuldeep;Menzen, Mark H.;Gosens, Reinoud
通讯作者：
Gosens, Reinoud
影响因子：
24.3
作者：
Kim, Young-Min;Kim, Hyekang;Lee, Seung-Woo
通讯作者：
Lee, Seung-Woo