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 August 1, 2019; First published May 21, 2019
Citation Information: J Clin Invest. 2019;129(8):3264-3276. https://doi.org/10.1172/JCI123540.
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Research Article Oncology

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

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

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Figure 2

T cell infiltration of αKO tumors and the requirement of CD4+ and CD8+ T cells for αKO tumor regression.

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T cell infiltration of αKO tumors and the requirement of CD4+ and CD8+ T...
(A and B) WT, αKO, or EgfrKO cells (0.5 million) were implanted in the head of the pancreas of B6 mice, and pancreata were harvested 10 days later (EgfrKO, n = 3; WT and αKO, n = 4). (A) Sections were stained with H&E, or IHC was performed with the indicated antibodies. Representative sections are shown. Scale bar: 100 μm. (B) Quantification of tumor-infiltrating cells positive for CD3, CD4, CD8, or F4/80. Bars indicate mean ± SEM. WT versus αKO, ***P = 0.0008, ****P = 0.0001, and *P = 0.0005 for CD3, CD4, and CD8, respectively (1-way ANOVA with Bonferroni’s post hoc test). (C–G) αKO cells (0.5 million) were implanted in the head of the pancreas of B6 mice injected with neutralizing CD4 and CD8 antibodies (αCD4/8, green) or PBS (control), or CD4KO (blue squares) or CD8KO (red diamonds) mice. (C) Quantification of luciferase signals from IVIS images of each mouse. Bars indicate median. **P < 0.005 (2-tailed Wilcoxon signed-rank test). (D) Kaplan-Meier survival curves for αCD4/8 (n = 5; median survival: 29 days), CD4KO (n = 9; median survival: 47 days), and CD8KO (n = 8; median survival: 37 days) mice implanted with αKO cells. P = 0.0017 (log-rank test, CD4KO vs CD8KO). (E) H&E-stained pancreatic sections from αCD4/8 and control mice. (F) IHC staining of pancreatic sections with antibodies against CD4 or CD8. Pancreata were collected from CD4KO or CD8KO mice at the humane endpoint. For comparison, sections of pancreata collected 10 days after implantation of B6 mice with 0.5 million αKO cells are shown. Scale bars: 100 μm. (G) Quantification of tumor-infiltrating CD4+ or CD8+ T cells from pancreatic sections.