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

Nithya Sivaram | Zendy; Patrick A. McLaughlin | Zendy; Han V. Han | Zendy; Oleksi Petrenko | Zendy; Yaping Jiang | Zendy; Lisa M. Ballou | Zendy; Kien Pham | Zendy; Chen Liu | Zendy; Adrianus WM Van der Velden | Zendy; Richard Z. Lin | Zendy

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

Author(s) -

Nithya Sivaram,

Patrick A. McLaughlin,

Han V. Han,

Oleksi Petrenko,

Yaping Jiang,

Lisa M. Ballou,

Kien Pham,

Chen Liu,

Adrianus WM Van der Velden,

Richard Z. Lin

Publication year - 2019

Publication title -

journal of clinical investigation

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.278

H-Index - 488

eISSN - 1558-8238

pISSN - 0021-9738

DOI - 10.1172/jci123540

Subject(s) - pancreatic cancer , immunogenicity , cancer research , cd80 , immunotherapy , t cell , adoptive cell transfer , tumor infiltrating lymphocytes , pancreatic tumor , biology , cancer immunotherapy , gene silencing , cancer , immune system , medicine , cytotoxic t cell , immunology , cd40 , in vitro , biochemistry , gene

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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