PPP2R1A mutations portend improved survival after cancer immunotherapy

Yibo Dai, Anne Knisely, Mitsutake Yano, Minghao Dang, Emily M. Hinchcliff, Sanghoon Lee, Annalyn Welp, Manoj Chelvanambi, Matthew Lastrapes, Heng Liu, Zhe Yuan, Chen Wang, Hao Nie, Stephanie Jean, Luis J. Montaner, Jiakai Hou, Ami Patel, Shrina Patel, Bryan Fellman, Ying Yuan, Baohua Sun, Renganayaki Krishna Pandurengan, Edwin Roger Parra Cuentas, Joseph Celestino, Yan Liu, Jinsong Liu, R. Tyler Hillman, Shannon N. Westin, Anil K. Sood, Pamela T. Soliman, Aaron Shafer, Larissa A. Meyer, David M. Gershenson, David Vining, Dhakshinamoorthy Ganeshan, Karen Lu, Jennifer A. Wargo, Weiyi Peng, Rugang Zhang (), Linghua Wang () and Amir A. Jazaeri ()
Additional contact information
Yibo Dai: The University of Texas MD Anderson Cancer Center
Anne Knisely: The University of Texas MD Anderson Cancer Center
Mitsutake Yano: The University of Texas MD Anderson Cancer Center
Minghao Dang: The University of Texas MD Anderson Cancer Center
Emily M. Hinchcliff: Robert H Lurie Comprehensive Cancer Center
Sanghoon Lee: The University of Texas MD Anderson Cancer Center
Annalyn Welp: University of Virginia School of Medicine
Manoj Chelvanambi: The University of Texas MD Anderson Cancer Center
Matthew Lastrapes: The University of Texas MD Anderson Cancer Center
Heng Liu: The Wistar Institute
Zhe Yuan: The Wistar Institute
Chen Wang: The University of Texas MD Anderson Cancer Center
Hao Nie: The University of Texas MD Anderson Cancer Center
Stephanie Jean: Helen F. Graham Cancer Center & Research Institute
Luis J. Montaner: The Wistar Institute
Jiakai Hou: University of Houston
Ami Patel: The University of Texas MD Anderson Cancer Center
Shrina Patel: The University of Texas MD Anderson Cancer Center
Bryan Fellman: The University of Texas MD Anderson Cancer Center
Ying Yuan: The University of Texas MD Anderson Cancer Center
Baohua Sun: The University of Texas MD Anderson Cancer Center
Renganayaki Krishna Pandurengan: The University of Texas MD Anderson Cancer Center
Edwin Roger Parra Cuentas: The University of Texas MD Anderson Cancer Center
Joseph Celestino: The University of Texas MD Anderson Cancer Center
Yan Liu: The University of Texas MD Anderson Cancer Center
Jinsong Liu: The University of Texas MD Anderson Cancer Center
R. Tyler Hillman: The University of Texas MD Anderson Cancer Center
Shannon N. Westin: The University of Texas MD Anderson Cancer Center
Anil K. Sood: The University of Texas MD Anderson Cancer Center
Pamela T. Soliman: The University of Texas MD Anderson Cancer Center
Aaron Shafer: The University of Texas MD Anderson Cancer Center
Larissa A. Meyer: The University of Texas MD Anderson Cancer Center
David M. Gershenson: The University of Texas MD Anderson Cancer Center
David Vining: The University of Texas MD Anderson Cancer Center
Dhakshinamoorthy Ganeshan: The University of Texas MD Anderson Cancer Center
Karen Lu: The University of Texas MD Anderson Cancer Center
Jennifer A. Wargo: The University of Texas MD Anderson Cancer Center
Weiyi Peng: University of Houston
Rugang Zhang: The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences
Linghua Wang: The University of Texas MD Anderson Cancer Center
Amir A. Jazaeri: The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences

Nature, 2025, vol. 644, issue 8076, 537-546

Abstract: 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 outcomes1–5. 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 therapies6–8. 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.

Date: 2025
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DOI: 10.1038/s41586-025-09203-8

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