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.
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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 4

PIK3CA regulates cell surface expression of MHC I and CD80 in KPC cells.

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PIK3CA regulates cell surface expression of MHC I and CD80 in KPC cells....
Flow cytometric analysis of cell surface levels of (A) H-2Kb and (B) CD80 in WT and αKO cells. The left panels show representative histograms and the right graphs show the mean ± SEM of the geometric means (geo. mean) of each flow cytometry distribution. H-2Kb, n = 4; CD80, n = 3. ***P = 0.0007 (unpaired t test). (C) qRT-PCR analysis of mRNA expression of H-2Kb, B2m, and CD80 in WT and αKO cells. Gene expression changes were normalized to Hprt. Graph shows mean ± SEM (n = 6). ****P < 0.0001 (unpaired t test). (D–F) B6 mice were implanted with 0.5 million αKO/shB2m, αKO/CD80KO, or αKO/CD80KO+shB2m cells in the head of the pancreas and tumor growth was monitored by IVIS imaging. (D) Kaplan-Meier survival curves for αKO/shB2m, αKO/CD80KO, and αKO/CD80KO+shB2m mice. *A single mouse was euthanized for histology and removed from the study. Median survival: αKO/shB2m, 110.5 days; αKO/CD80KO+shB2m, 87.5 days. All αKO/CD80KO mice were alive at 115 days. P = 0.0026 (log-rank test). (E) Representative H&E and IHC images of pancreatic sections from αKO/shB2m or αKO/CD80KO+shB2m mice that died of tumor progression. Scale bar: 100 μm. (F) Representative H&E-stained pancreatic sections from a single αKO/shB2m mouse or αKO/CD80KO mice euthanized at 101 or 160 days, respectively. Scale bar: 100 μm.