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
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
Nature. 2025 Jul 2. doi: 10.1038/s41586-025-09203-8.
Immune checkpoint blockade (ICB) therapy is effective against many cancers, although resistance remains a major issue and new strategies are needed to improve clinical outcomes. 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 therapies. 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 CD45ROCD8 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.
免疫检查点阻断（ICB）疗法对许多癌症有效，尽管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。在这里，我们研究了一组卵巢透明细胞癌患者的ICB反应，这种癌症类型带来了相当大的临床挑战且缺乏有效治疗方法。我们观察到携带PPP2R1A突变的肿瘤患者的总生存期和无进展生存期显著延长。重要的是，我们的发现在多个癌症类型的其他接受ICB治疗的患者队列中得到了验证。肿瘤活检的转化分析表明，在基线时IFNγ信号增强，存在三级淋巴结构，以及在PPP2R1A突变肿瘤接受ICB治疗后，肿瘤周围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（通过药物抑制或基因改造）与几种形式的免疫治疗（包括嵌合抗原受体（CAR）-T细胞疗法和ICB）治疗时生存率的提高相关。这些研究结果表明，靶向PPP2R1A进行治疗可能是改善ICB或其他形式免疫治疗后患者预后的有效策略，尽管还需要更多的机制和治疗方面的见解。
