PIK3CA in KrasG12D/Trp53R172H Tumor Cells Promotes Immune Evasion by Limiting Infiltration of T Cells in a Model of Pancreatic Cancer

Sivaram, N.; McLaughlin, P. A.; Han, H. V.; Petrenko, O.; Jiang, Y.-P.; Ballou, L. M.; Pham, K.; Liu, C.; Van der Velden, A. W. M.; Lin, R. Z.

doi:10.1101/521831

bioRxiv · 10.1101/521831

PIK3CA in KrasG12D/Trp53R172H Tumor Cells Promotes Immune Evasion by Limiting Infiltration of T Cells in a Model of Pancreatic Cancer

Sivaram, N.·McLaughlin, P. A.·Han, H. V.·Petrenko, O.·Jiang, Y.-P.·Ballou, L. M.·Pham, K.·Liu, C.·Van der Velden, A. W. M.·Lin, R. Z.

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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 leads to 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 progress and kill all of the animals. Adoptive transfer of tumor antigen-experienced T cells eliminates Pik3ca-null tumors in immunodeficient mice. Loss of PIK3CA or inhibition of its effector, AKT, increases the expression of MHC Class I and CD80 on tumor cells. These changes contribute to the increased susceptibility of Pik3ca-null tumors to T cell surveillance. These 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.\n\nSIGNIFICANCEPIK3CA-AKT signaling in pancreatic cancer cells limits T cell infiltration and clearance of tumors by suppressing the surface expression of MHC Class I and CD80. Targeting the PIK3CA-AKT pathway in tumor cells provides a new avenue for discovery of novel pancreatic cancer immunotherapies.

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Sivaram, N., McLaughlin, P. A., Han, H. V., Petrenko, O., Jiang, Y.-P., Ballou, L. M., Pham, K., Liu, C., Van der Velden, A. W. M., Lin, R. Z.. 2019-01-15. PIK3CA in KrasG12D/Trp53R172H Tumor Cells Promotes Immune Evasion by Limiting Infiltration of T Cells in a Model of Pancreatic Cancer. https://doi.org/10.1101/521831

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