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美国科罗拉多大学Sana D. Karam研究组发现，同时靶向PD-1和IL-2Rβγ的放射治疗抑制胰腺癌的生长和转移。2023年4月27日出版的《癌细胞》发表了这项成果。

在胰腺导管腺癌(PDAC)患者中，他们发现放射治疗(RT)的反应特征是IL-2Rβ和IL-2Rγ升高以及IL-2Rα表达降低。双特异性的PD1-IL2v是一种PD-1靶向的IL-2变体(IL-2v)免疫细胞因子，其工程化的IL-2靶向PD-1并消除IL-2Rα的结合，从而增强肿瘤抗原特异性T细胞的激活，同时降低调节性T细胞(Treg)的抑制。在原位PDAC KPC驱动的肿瘤模型中使用PD1-IL2v，他们发现局部和转移性生存显著改善，肿瘤浸润性CD8+ T细胞亚群显著增加，具有转录和代谢活性表型，抗原特异性CD8+ T细胞优先活化。

与单剂量RT联合，PD1-IL2v治疗可导致多功能CD8+ T细胞，T细胞干性，肿瘤特异性记忆免疫反应，自然杀伤(NK)细胞活化和Tregs降低的稳健，持久的扩增。这些数据表明，PD1-IL2v在PDAC中具有深远的局部和远处响应。

附：英文原文

Title: Simultaneous targeting of PD-1 and IL-2Rβγ with radiation therapy inhibits pancreatic cancer growth and metastasis

Author: Miles Piper, Maureen Hoen, Laurel B. Darragh, Michael W. Knitz, Diemmy Nguyen, Jacob Gadwa, Greta Durini, Idil Karakoc, Abby Grier, Brooke Neupert, Benjamin Van Court, Khalid N.M. Abdelazeem, Justin Yu, Nicholas A. Olimpo, Sophia Corbo, Richard Blake Ross, Tiffany T. Pham, Molishree Joshi, Ross M. Kedl, Anthony J. Saviola, Maria Amann, Pablo Umaa, Laura Codarri Deak, Christian Klein, Angelo D’Alessandro, Sana D. Karam

Issue&Volume: 2023-04-27

Abstract: In pancreatic ductal adenocarcinoma (PDAC) patients, we show that response to radiation therapy (RT) is characterized by increased IL-2Rβ and IL-2Rγ along with decreased IL-2Rα expression. The bispecific PD1-IL2v is a PD-1-targeted IL-2 variant (IL-2v) immunocytokine with engineered IL-2 cis targeted to PD-1 and abolished IL-2Rα binding, which enhances tumor-antigen-specific T cell activation while reducing regulatory T cell (Treg) suppression. Using PD1-IL2v in orthotopic PDAC KPC-driven tumor models, we show marked improvement in local and metastatic survival, along with a profound increase in tumor-infiltrating CD8+ T cell subsets with a transcriptionally and metabolically active phenotype and preferential activation of antigen-specific CD8+ T cells. In combination with single-dose RT, PD1-IL2v treatment results in a robust, durable expansion of polyfunctional CD8+ T cells, T cell stemness, tumor-specific memory immune response, natural killer (NK) cell activation, and decreased Tregs. These data show that PD1-IL2v leads to profound local and distant response in PDAC.

DOI: 10.1016/j.ccell.2023.04.001

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00117-4

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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