In a syngeneic orthotopic implantation model of KRASG12D/Trp53R172H-driven pancreatic cancer, Sivaram et al. found that Pik3ca-deficient tumor cell lines were cleared by infiltrating CD8+ and CD4+ T cells in immunocompetent mice, resulting in complete regression and 100% survival. Similarly, prophylactic or therapeutic adoptive transfer of tumor-specific T cells protected SCID mice from Pik3ca-deficient tumors. Reduced Pik3ca expression enhanced tumor cell immunogenicity through upregulated expression of MHC-I and CD80, an effect mediated by inhibition of downstream AKT and confirmed with an AKT inhibitor.
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 Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)
Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)
