Leveraging the Treg-intrinsic CTLA4-PKCη signaling pathway for cancer immunotherapy.
Leveraging the Treg-intrinsic CTLA4-PKCη signaling pathway for cancer immunotherapy.
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利用Treg-内在CTLA 4-PKCη信号通路进行癌症免疫治疗。
DOI：
10.1136/jitc-2021-002792
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发表时间：
2021-09
影响因子：
10.9
通讯作者：
Altman A
中科院分区：
文献类型：
--
作者：
Liu HY;Pedros C;Kong KF;Canonigo-Balancio AJ;Xue W;Altman A
我们之前的研究揭示了一种新型 CTLA4-蛋白激酶 C-eta (PKCη) 信号轴在介导调节性 T 细胞 (Treg) 抗肿瘤免疫抑制活性中的关键作用。这些研究在肿瘤植入之前将种系 PKCη 缺陷 (Prkch−/−) Tregs 过继转移到 Prkch+/+ 小鼠中。在这里，我们将这些发现扩展到生物学和临床上更相关的背景中。我们分析了 Treg 特异性或 CD8+ T 细胞特异性 Prkch 缺失的完整荷瘤小鼠中 PKCη 在抗肿瘤免疫和肿瘤微环境 (TME) 中的作用，包括在组合治疗的治疗模型中。除了测量肿瘤生长之外，我们还分析了肿瘤浸润免疫细胞的表型和功能属性，特别是 Tregs 和树突状细胞 (DC)。使用两种小鼠可移植癌症模型和基因工程原发性肝细胞癌 (HCC) 模型，我们首先发现，Treg 特异性 Prkch 缺失的小鼠表现出 B16-F10 黑色素瘤和 TRAMP-C1 腺癌肿瘤的生长显着减少。肿瘤生长减少与免疫抑制性 TME 减弱相关，肿瘤浸润 CD8+ 效应 T 细胞数量和功能增加以及瘤内 DC 上共刺激配体 CD86 表达升高表明。相比之下，CD8+ T细胞特异性Prkch缺失对肿瘤生长或CD8+效应T细胞的丰度和功能没有影响，这与Prkch−/− CD8+ T细胞响应体外多克隆或特异性抗原刺激而正常增殖的发现一致。在种系或 Treg 特异性 Prkch 缺失的小鼠中也发现了类似的有益抗肿瘤作用，这些小鼠被诱导发展为原发性 HCC。最后，使用治疗模型，我们发现，由 Treg 特异性 Prkch 缺失或用受辐射的表达 Fms 样酪氨酸激酶 3 配体 (Flt3L) 的 B16-F10 肿瘤细胞接种疫苗组成的单一疗法在肿瘤植入后显着延迟了肿瘤生长。这种效果在接受两种免疫疗法组合的小鼠中更为明显。这些发现证明了 PKCη 抑制作为治疗癌症患者的可行临床方法的潜在效用，特别是与辅助疗法相结合时。
Our previous studies revealed a critical role of a novel CTLA4-protein kinase C-eta (PKCη) signaling axis in mediating the suppressive activity of regulatory T cells (Tregs) in antitumor immunity. These studies have employed adoptive transfer of germline PKCη-deficient (Prkch−/−) Tregs into Prkch+/+ mice prior to tumor implantation. Here, we extended these findings into a biologically and clinically more relevant context. We have analyzed the role of PKCη in antitumor immunity and the tumor microenvironment (TME) in intact tumor-bearing mice with Treg-specific or CD8+ T cell-specific Prkch deletion, including in a therapeutic model of combinatorial treatment. In addition to measuring tumor growth, we analyzed the phenotype and functional attributes of tumor-infiltrating immune cells, particularly Tregs and dendritic cells (DCs). Using two models of mouse transplantable cancer and a genetically engineered autochthonous hepatocellular carcinoma (HCC) model, we found, first, that mice with Treg-specific Prkch deletion displayed a significantly reduced growth of B16–F10 melanoma and TRAMP-C1 adenocarcinoma tumors. Tumor growth reduction was associated with a less immunosuppressive TME, indicated by increased numbers and function of tumor-infiltrating CD8+ effector T cells and elevated expression of the costimulatory ligand CD86 on intratumoral DCs. In contrast, CD8+ T cell-specific Prkch deletion had no effect on tumor growth or the abundance and functionality of CD8+ effector T cells, consistent with findings that Prkch−/− CD8+ T cells proliferated normally in response to in vitro polyclonal or specific antigen stimulation. Similar beneficial antitumor effects were found in mice with germline or Treg-specific Prkch deletion that were induced to develop an autochthonous HCC. Lastly, using a therapeutic model, we found that monotherapies consisting of Treg-specific Prkch deletion or vaccination with irradiated Fms-like tyrosine kinase 3 ligand (Flt3L)-expressing B16–F10 tumor cells post-tumor implantation significantly delayed tumor growth. This effect was more pronounced in mice receiving a combination of the two immunotherapies. These findings demonstrate the potential utility of PKCη inhibition as a viable clinical approach to treat patients with cancer, especially when combined with adjuvant therapies.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
DOI：
10.1126/science.1202947
发表时间：
2011-04-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Qureshi OS;Zheng Y;Nakamura K;Attridge K;Manzotti C;Schmidt EM;Baker J;Jeffery LE;Kaur S;Briggs Z;Hou TZ;Futter CE;Anderson G;Walker LS;Sansom DM
通讯作者：
Sansom DM
影响因子：
29.4
作者：
Laurent-Puig, P;Legoix, P;Zucman-Rossi, J
通讯作者：
Zucman-Rossi, J
白介素10在抑制肠炎的调节T细胞功能中的重要作用。
影响因子：
15.3
作者：
Asseman, C;Mauze, S;Leach, M W;Coffman, R L;Powrie, F
通讯作者：
Powrie, F