德克萨斯大学Amir A. Jazaeri研究小组近日取得一项新成果。经过不懈努力，他们报道了PPP2R1A突变预示着癌症免疫治疗后生存率的提高。2025年7月2日出版的《自然》发表了这项成果。

在这里，研究小组研究了一组卵巢透明细胞癌患者的ICB反应-一种具有相当大的临床挑战且缺乏有效治疗的癌症类型。该课题组观察到PPP2R1A突变肿瘤患者的总生存期和无进展生存期显著延长。重要的是，他们的发现在不同癌症类型的其他接受ICB治疗的患者队列中得到了验证。来自肿瘤活检的翻译分析表明，在PPP2R1A突变的肿瘤中，ICB治疗后，IFNγ信号传导增强，基线处存在三级淋巴样结构，以及肿瘤附近CD45RO⁺CD8⁺ T细胞的免疫浸润和扩增增强。平行的临床前研究表明，在体外和体内模型中，靶向PPP2R1A（通过药理抑制或遗传修饰）与几种免疫疗法（包括嵌合抗原受体(CAR)-T细胞疗法和ICB）治疗环境下的生存率提高有关。这些研究的结果表明，PPP2R1A的治疗靶向可能是改善ICB或其他形式免疫治疗后患者预后的有效策略，尽管需要额外的机制和治疗见解。

研究人员表示，免疫检查点阻断（ICB）治疗对许多癌症有效，但是耐药性仍然是一个主要问题，需要新的策略来改善临床结果。

附：英文原文

Title: PPP2R1A mutations portend improved survival after cancer immunotherapy

Author: Dai, Yibo, Knisely, Anne, Yano, Mitsutake, Dang, Minghao, Hinchcliff, Emily M., Lee, Sanghoon, Welp, Annalyn, Chelvanambi, Manoj, Lastrapes, Matthew, Liu, Heng, Yuan, Zhe, Wang, Chen, Nie, Hao, Jean, Stephanie, Montaner, Luis J., Hou, Jiakai, Patel, Ami, Patel, Shrina, Fellman, Bryan, Yuan, Ying, Sun, Baohua, Pandurengan, Renganayaki Krishna, Cuentas, Edwin Roger Parra, Celestino, Joseph, Liu, Yan, Liu, Jinsong, Hillman, R. Tyler, Westin, Shannon N., Sood, Anil K., Soliman, Pamela T., Shafer, Aaron, Meyer, Larissa A., Gershenson, David M., Vining, David, Ganeshan, Dhakshinamoorthy, Lu, Karen, Wargo, Jennifer A., Peng, Weiyi, Zhang, Rugang, Wang, Linghua, Jazaeri, Amir A.

Issue&Volume: 2025-07-02

Abstract: Immune checkpoint blockade (ICB) therapy is effective against many cancers, although resistance remains a major issue and new strategies are needed to improve clinical outcomes1,2,3,4,5. Here we studied ICB response in a cohort of patients with ovarian clear cell carcinoma—a cancer type that poses considerable clinical challenges and lacks effective therapies6,7,8. We observed significantly prolonged overall survival and progression-free survival in patients with tumours with PPP2R1A mutations. Importantly, our findings were validated in additional ICB-treated patient cohorts across multiple cancer types. Translational analyses from tumour biopsies demonstrated enhanced IFNγ signalling, and the presence of tertiary lymphoid structures at the baseline, as well as enhanced immune infiltration and expansion of CD45RO+CD8+ T cells in the tumour neighbourhood after ICB treatment in PPP2R1A-mutated tumours. Parallel preclinical investigations showed that targeting PPP2R1A (by pharmacological inhibition or genetic modifications) in in vitro and in vivo models was associated with improved survival in the setting of treatment with several forms of immunotherapy, including chimeric antigen receptor (CAR)-T cell therapy and ICB. The results from these studies suggest that therapeutic targeting of PPP2R1A may represent an effective strategy to improve patient outcomes after ICB or other forms of immunotherapy, although additional mechanistic and therapeutic insights are needed.

DOI: 10.1038/s41586-025-09203-8

Source: https://www.nature.com/articles/s41586-025-09203-8