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

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

doi:10.1172/JCI123540

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

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

New Jersey Medical School (NJMS), Pathology

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

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 Kras^G12D/ Trp53^R172H-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.

Original language	English (US)
Pages (from-to)	3264-3276
Number of pages	13
Journal	Journal of Clinical Investigation
Volume	129
Issue number	8
DOIs	https://doi.org/10.1172/JCI123540
State	Published - Aug 1 2019

All Science Journal Classification (ASJC) codes

Medicine(all)

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10.1172/JCI123540

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@article{a6911b6163ec464b888b003ad85f9dd0,

title = "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.",

author = "Nithya Sivaram and McLaughlin, {Patrick A.} and Han, {Han V.} and Oleksi Petrenko and Jiang, {Ya Ping} and Ballou, {Lisa M.} and Kien Pham and Chen Liu and {Van Der Velden}, {Adrianus W.M.} and Lin, {Richard Z.}",

note = "Funding Information: This work was funded by NIH grants DK108989 (to RZL), CA194836 (to RZL), and AI101221 (to AWMV), and a VA Merit Award BX004083 (to RZL). RPPA was performed by the RPPA core facility at MD Anderson Cancer Center, funded by NCI grant CA16672. We thank Juei-Suei Chen for help with H&E staining and immunohistochemistry. Publisher Copyright: {\textcopyright} 2019, American Society for Clinical Investigation.",

year = "2019",

month = aug,

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doi = "10.1172/JCI123540",

language = "English (US)",

volume = "129",

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journal = "Journal of Clinical Investigation",

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T1 - Tumor-intrinsic PIK3CA represses tumor immunogenicity in a model of pancreatic cancer

AU - Sivaram, Nithya

AU - McLaughlin, Patrick A.

AU - Han, Han V.

AU - Petrenko, Oleksi

AU - Jiang, Ya Ping

AU - Ballou, Lisa M.

AU - Pham, Kien

AU - Liu, Chen

AU - Van Der Velden, Adrianus W.M.

AU - Lin, Richard Z.

N1 - Funding Information: This work was funded by NIH grants DK108989 (to RZL), CA194836 (to RZL), and AI101221 (to AWMV), and a VA Merit Award BX004083 (to RZL). RPPA was performed by the RPPA core facility at MD Anderson Cancer Center, funded by NCI grant CA16672. We thank Juei-Suei Chen for help with H&E staining and immunohistochemistry. Publisher Copyright: © 2019, American Society for Clinical Investigation.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

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JO - Journal of Clinical Investigation

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

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