Open AccessTumor-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 W. M. van der Velden,
Richard Z. Lin
Publication year - 2019
Publication title -
the journal of clinical investigation/the 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 , pancreatic tumor , tumor infiltrating lymphocytes , cancer immunotherapy , biology , cancer , immune system , medicine , cytotoxic t cell , immunology , cd40 , in vitro , biochemistry
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.