Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Tumor-intrinsic PIK3CA represses tumor immunogenicity in a model of pancreatic cancer
Nithya Sivaram, … , Adrianus W.M. van der Velden, Richard Z. Lin
Nithya Sivaram, … , Adrianus W.M. van der Velden, Richard Z. Lin
Published May 21, 2019
Citation Information: J Clin Invest. 2019;129(8):3264-3276. https://doi.org/10.1172/JCI123540.
View: Text | PDF
Research Article Oncology

Tumor-intrinsic PIK3CA represses tumor immunogenicity in a model of pancreatic cancer

  • Text
  • PDF
Abstract

The presence of tumor-infiltrating T cells is associated with favorable patient outcomes, yet most pancreatic cancers are immunologically silent and resistant to currently available immunotherapies. Here we show using a syngeneic orthotopic implantation model of pancreatic cancer that Pik3ca regulates tumor immunogenicity. Genetic silencing of Pik3ca in KrasG12D/Trp53R172H-driven pancreatic tumors resulted in infiltration of T cells, complete tumor regression, and 100% survival of immunocompetent host mice. By contrast, Pik3ca-null tumors implanted in T cell–deficient mice progressed and killed all of the animals. Adoptive transfer of tumor antigen–experienced T cells eliminated Pik3ca-null tumors in immunodeficient mice. Loss of PIK3CA or inhibition of its effector AKT increased the expression of MHC class I and CD80 on tumor cells. These changes contributed to the increased susceptibility of Pik3ca-null tumors to T cell surveillance. Our results indicate that tumor cell PIK3CA-AKT signaling limits T cell recognition and clearance of pancreatic cancer cells. Strategies that target this pathway may yield an effective immunotherapy for this cancer.

Authors

Nithya Sivaram, Patrick A. McLaughlin, Han V. Han, Oleksi Petrenko, Ya-Ping Jiang, Lisa M. Ballou, Kien Pham, Chen Liu, Adrianus W.M. van der Velden, Richard Z. Lin

×

Figure 1

Proliferation of αKO pancreatic cancer cells in vitro and regression in vivo.

Options: View larger image (or click on image) Download as PowerPoint
Proliferation of αKO pancreatic cancer cells in vitro and regression in ...
(A) Proliferation rates of KPC cell lines in standard 2D culture. Cells plated in triplicate were counted at the times indicated (mean ± SEM; n = 3). *P = 0.0191, WT versus αKO; **P = 0.375, WT versus EgfrKO (1-way ANOVA with Bonferroni’s post hoc test). (B) Percentage of cells positive for annexin V staining at the 4-day time point in A (mean ± SEM, n = 3). P = 0.18, WT versus αKO; P = 0.12, WT versus EgfrKO (1-way ANOVA with Bonferroni’s post hoc test). (C) Representative light microscopy images (×40 magnification) of spheroids formed after 5 days in 3D methylcellulose culture. (D) Cells (0.5 million) were implanted in the head of the pancreas of B6 mice. Tumor growth was monitored by IVIS imaging of the luciferase signal on days 1, 7, and 14 after implantation. Representative images of 3 mice in each group are shown. (E) Quantification of luciferase signals from each mouse. The bars indicate median. On day 7, ***P = 0.0006, WT versus αKO and P > 0.9, WT versus EgfrKO; on day 14, ****P < 0.0001, WT versus αKO and P = 0.0618, WT versus EgfrKO (Kruskal-Wallis test with Dunn’s post hoc test). (F) Kaplan-Meier survival curves for B6 mice implanted with the indicated cell lines. Median survival: WT, 16 days (n = 16); EgfrKO, 17 days (n = 10); all αKO mice were alive at day 80 (n = 17). P < 0.0001, WT versus αKO (log-rank test). (G) H&E-stained sections of pancreatic tissue collected at the indicated times after cell implantation in B6 mice. Scale bar: 100 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts