Overcoming Immunotherapy Resistance by Targeting the Tumor-Intrinsic NLRP3-HSP70 Signaling Axis.
Overcoming Immunotherapy Resistance by Targeting the Tumor-Intrinsic NLRP3-HSP70 Signaling Axis.
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DOI：
10.3390/cancers13194753
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发表时间：
2021-09-23
期刊：
影响因子：
5.2
通讯作者：
Hanks BA
中科院分区：
文献类型：
--
作者：
Theivanthiran B;Haykal T;Cao L;Holtzhausen A;Plebanek M;DeVito NC;Hanks BA
肿瘤内源性NLRP 3炎性小体是一种新认识到的调节肿瘤免疫反应的参与者，并有望为肿瘤如何对免疫治疗作出反应提供新的见解。这篇简短的综述讨论了最近的数据，这些数据描述了肿瘤内源性NLRP 3炎性体的激活如何有助于免疫逃避，以及这一途径可以为免疫肿瘤学领域提供什么，包括能够增强对检查点抑制剂治疗的反应的药理学靶点和指示哪些肿瘤可能最容易受到这些新治疗策略影响的预测性生物标志物。肿瘤内源性NOD样受体家族，含pyrin-domain-containing-3（NLRP 3）炎性体，在调节肿瘤微环境（TME）中的免疫抑制性髓样细胞群中起重要作用。虽然先前的研究已经描述了这种炎性小体在驱动促肿瘤发生机制中的激活，但新出现的数据现在揭示了肿瘤NLRP 3炎性小体和热休克蛋白-70（HSP 70）的下游释放，以调节抗肿瘤免疫并有助于对抗PD-1免疫疗法的适应性抗性的发展。影响NLRP 3信号传导轴活性的遗传改变可能影响T细胞介导的肿瘤细胞杀伤，并可能表明哪些肿瘤依赖于该途径进行免疫逃逸。这些研究表明，NLRP 3炎性小体及其分泌产物HSP 70代表了在TME中操纵先天免疫细胞群同时增强对抗PD-1免疫疗法的应答的有希望的药理学靶标。需要进一步的研究来更好地了解NLRP 3的肿瘤特异性调节机制，以开发能够增强对检查点抑制剂免疫治疗的反应，同时最大限度地减少不必要的脱靶效应的肿瘤选择性药理学策略。即将进行的临床试验的执行，研究这种克服抗PD-1耐药性的策略，有望为这种途径在免疫肿瘤学中的作用提供新的见解。
The tumor-intrinsic NLRP3 inflammasome is a newly recognized player in the regulation of tumor-directed immune responses and promises to provide fresh insight into how tumors respond to immunotherapy. This brief review discusses recent data describing how activation of the tumor-intrinsic NLRP3 inflammasome contributes to immune evasion and what this pathway may provide to the field of immuno-oncology both in terms of pharmacologic targets capable of boosting responses to checkpoint inhibitor therapies and predictive biomarkers indicating which tumors may be most susceptible to these new therapeutic strategies. The tumor-intrinsic NOD-like receptor family, pyrin-domain-containing-3 (NLRP3) inflammasome, plays an important role in regulating immunosuppressive myeloid cell populations in the tumor microenvironment (TME). While prior studies have described the activation of this inflammasome in driving pro-tumorigenic mechanisms, emerging data is now revealing the tumor NLRP3 inflammasome and the downstream release of heat shock protein-70 (HSP70) to regulate anti-tumor immunity and contribute to the development of adaptive resistance to anti-PD-1 immunotherapy. Genetic alterations that influence the activity of the NLRP3 signaling axis are likely to impact T cell-mediated tumor cell killing and may indicate which tumors rely on this pathway for immune escape. These studies suggest that the NLRP3 inflammasome and its secreted product, HSP70, represent promising pharmacologic targets for manipulating innate immune cell populations in the TME while enhancing responses to anti-PD-1 immunotherapy. Additional studies are needed to better understand tumor-specific regulatory mechanisms of NLRP3 to enable the development of tumor-selective pharmacologic strategies capable of augmenting responses to checkpoint inhibitor immunotherapy while minimizing unwanted off-target effects. The execution of upcoming clinical trials investigating this strategy to overcome anti-PD-1 resistance promises to provide novel insight into the role of this pathway in immuno-oncology.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
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：
10.1161/atvbaha.117.310097
发表时间：
2017-11
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Baylis RA;Gomez D;Mallat Z;Pasterkamp G;Owens GK
通讯作者：
Owens GK
DOI：
10.1084/jem.20161707
发表时间：
2017-06-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Daley D;Mani VR;Mohan N;Akkad N;Pandian GSDB;Savadkar S;Lee KB;Torres-Hernandez A;Aykut B;Diskin B;Wang W;Farooq MS;Mahmud AI;Werba G;Morales EJ;Lall S;Wadowski BJ;Rubin AG;Berman ME;Narayanan R;Hundeyin M;Miller G
通讯作者：
Miller G
影响因子：
8.8
作者：
Gato-Canas, Maria;Zuazo, Miren;Escors, David
通讯作者：
Escors, David