Selective targeting of IL2Rβγ combined with radiotherapy triggers CD8- and NK-mediated immunity, abrogating metastasis in HNSCC.
Selective targeting of IL2Rβγ combined with radiotherapy triggers CD8- and NK-mediated immunity, abrogating metastasis in HNSCC.
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DOI：
10.1016/j.xcrm.2023.101150
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发表时间：
2023-08-15
影响因子：
14.3
通讯作者：
Karam, Sana D.
中科院分区：
文献类型：
--
作者：
Gadwa, Jacob;Amann, Maria;Bickett, Thomas E.;Knitz, Michael W.;Darragh, Laurel B.;Piper, Miles;Van Court, Benjamin;Bukkapatnam, Sanjana;Pham, Tiffany T.;Wang, Xiao-Jing;Saviola, Anthony J.;Deak, Laura Codarri;Umana, Pablo;Klein, Christian;D'Alessandro, Angelo;Karam, Sana D.
癌症免疫疗法的实施在头颈部鳞状细胞癌（HNSCC）中的临床成功有限。受到高亲和力IL-2Rα的调节T细胞（TREG）的限制。通过IL-2Rβγ信号在表达PD-1的细胞上。 2Rα激活Tregs。 PD1-IL2V驱动全身性激活和循环和肿瘤浸润的细胞毒性T细胞和NK细胞的扩展，同时限制了Treg介导的免疫抑制作用。
RT和PD1-IL2V组合驱动肿瘤回归并增加生存
RT+ PD1-IL2V启动肿瘤反应性T细胞反应，同时限制Treg抑制
RT+ PD1-IL2V增强了NK细胞激活受体表达和细胞毒性
改善NK免疫监视控制可转移到肺部的转移性扩散
在头颈癌的激进模型中，Gadwa等。原发性和遥远的肿瘤控制。
The implementation of cancer immunotherapies has seen limited clinical success in head and neck squamous cell carcinoma (HNSCC). Interleukin-2 (IL-2), which modulates the survival and functionality of lymphocytes, is an attractive target for new immunotherapies but one that is limited by presence of regulatory T cells (Tregs) expressing the high-affinity IL-2Rα. The bispecific immunocytokine PD1-IL2v preferentially delivers IL-2 signaling through IL-2Rβγ on PD-1-expressing cells. Selectively targeting the intermediate-affinity IL-2Rβγ can be leveraged to induce anti-tumor immune responses in effector T cells and natural killer (NK) cells while limiting the negative regulation of IL-2Rα activation on Tregs. Using radiation therapy (RT) in combination with PD1-IL2v improves local tumor control and survival, and controls metastatic spread in orthotopic HNSCC tumor models. PD1-IL2v drives systemic activation and expansion of circulating and tumor-infiltrating cytotoxic T cells and NK cells while limiting Treg-mediated immunosuppression. These data show that PD1-L2v induces durable systemic tumor control in HNSCC. Combined RT and PD1-IL2v drives tumor regression and increases survival RT + PD1-IL2v initiates tumor-reactive T cell responses while limiting Treg suppression RT + PD1-IL2v enhances NK cell activating receptor expression and cytotoxicity Improved NK immunosurveillance controls metastatic spread to lungs In aggressive models of head and neck cancer, Gadwa et al. demonstrate that radiation therapy combined with the immunocytokine PD1-IL2v elicits a robust anti-tumor immune response by invigorating T cell and natural killer cell activation and expansion across multiple immunological compartments, resulting in superior primary and distant tumor control.
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DOI：
10.1158/1078-0432.ccr-21-0971
发表时间：
2021-11-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Bickett TE;Knitz M;Darragh LB;Bhatia S;Van Court B;Gadwa J;Bhuvane S;Piper M;Nguyen D;Tu H;Lenz L;Clambey ET;Barry K;Karam SD
通讯作者：
Karam SD
影响因子：
16.6
作者：
Koyama S;Akbay EA;Li YY;Herter-Sprie GS;Buczkowski KA;Richards WG;Gandhi L;Redig AJ;Rodig SJ;Asahina H;Jones RE;Kulkarni MM;Kuraguchi M;Palakurthi S;Fecci PE;Johnson BE;Janne PA;Engelman JA;Gangadharan SP;Costa DB;Freeman GJ;Bueno R;Hodi FS;Dranoff G;Wong KK;Hammerman PS
通讯作者：
Hammerman PS
影响因子：
4.7
作者：
Sun Y;Xu Z;Jiang J;Xu T;Xu J;Liu P
通讯作者：
Liu P
影响因子：
6.4
作者：
Addison, EG;North, J;Lowdell, MW
通讯作者：
Lowdell, MW
影响因子：
20.3
作者：
Fiegler, Nathalie;Textor, Sonja;Cerwenka, Adelheid
通讯作者：
Cerwenka, Adelheid