2. Academic Validation
  3. PPP2R1A mutations portend improved survival after cancer immunotherapy

PPP2R1A mutations portend improved survival after cancer immunotherapy

  • Nature. 2025 Aug;644(8076):537-546. doi: 10.1038/s41586-025-09203-8.
Yibo Dai # 1 2,  Anne Knisely # 3,  Mitsutake Yano # 4,  Minghao Dang # 1,  Emily M Hinchcliff 5,  Sanghoon Lee 3,  Annalyn Welp 6,  Manoj Chelvanambi 7,  Matthew Lastrapes 7,  Heng Liu 8,  Zhe Yuan 8,  Chen Wang 4,  Hao Nie 4,  Stephanie Jean 9,  Luis J Montaner 8,  Jiakai Hou 10,  Ami Patel 3,  Shrina Patel 3,  Bryan Fellman 11,  Ying Yuan 11,  Baohua Sun 12,  Renganayaki Krishna Pandurengan 12,  Edwin Roger Parra Cuentas 12,  Joseph Celestino 3,  Yan Liu 13,  Jinsong Liu 13,  R Tyler Hillman 3,  Shannon N Westin 3,  Anil K Sood 3,  Pamela T Soliman 3,  Aaron Shafer 3,  Larissa A Meyer 3,  David M Gershenson 3,  David Vining 14,  Dhakshinamoorthy Ganeshan 14,  Karen Lu 3,  Jennifer A Wargo 1 2 7,  Weiyi Peng 10,  Rugang Zhang 15 16,  Linghua Wang 17 18 19 20,  Amir A Jazaeri 21 22
Affiliations

Affiliations

  • 1 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
  • 3 Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Northwestern University, Feinberg School of Medicine, Robert H Lurie Comprehensive Cancer Center, Chicago, IL, USA.
  • 6 University of Virginia School of Medicine, Charlottesville, VA, USA.
  • 7 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8 Immunology, Metastasis and Microenvironment Program, The Wistar Institute, Philadelphia, PA, USA.
  • 9 Helen F. Graham Cancer Center & Research Institute, Newark, DE, USA.
  • 10 Department of Biology & Biochemistry, University of Houston, Houston, TX, USA.
  • 11 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 12 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 13 Department of Anatomic Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 14 Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 15 The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA. RZhang11@mdanderson.org.
  • 16 Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. RZhang11@mdanderson.org.
  • 17 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. LWang22@mdanderson.org.
  • 18 The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA. LWang22@mdanderson.org.
  • 19 The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. LWang22@mdanderson.org.
  • 20 Institute for Data Science in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. LWang22@mdanderson.org.
  • 21 The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA. aajazaeri@mdanderson.org.
  • 22 Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. aajazaeri@mdanderson.org.
  • # Contributed equally.
PMID: 40604275 DOI: 10.1038/s41586-025-09203-8
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.

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