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 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.

KRAS drives immune evasion in a genetic model of pancreatic cancer

“…We also demonstrate that tumor tumor-intrinsic factors such as SMAD4 act as a barrier against tumor immune escape. As reported, growth of KRAS mutant pancreatic cancer cells with targeted inactivation of PIK3CA, a parallel branch of the KRAS signaling pathway, is also inhibited in syngeneic wild-type mice but not in nude mice due to the upregulation of MHC class I expression 58 . The results imply that the ability of mutant KRAS to modulate tumor immunity (via involvement of the RAF, PI3K, and MYC pathways) is an essential component of its oncogenicity, and that treatment of cancer will be improved by different modalities acting to simultaneously inhibit KRAS and activate immune pathways suppressed by cancer.…”

Understanding the immune landscape and tumor microenvironment of pancreatic cancer to improve immunotherapy

“…Phosophoinosotiol‐3‐kinase (PI3K) is a downstream effector of KRAS. The kinase, PI3KCA, has been implicated in driving reduced MHC class I and CD80 expression in pancreatic cancer cells resulting in impaired T cell recognition of tumor cells 33 . Understanding the tumor cell‐intrinsic properties of pancreatic cancer that drive immune evasion may lead to novel combination treatment approaches to increase the effectiveness of immunotherapy.…”

Overcoming resistance to immune checkpoint therapy in PTEN-null prostate cancer by sequential intermittent anti-PI3Kα/β/δ and anti-PD-1 treatment

“…Cancer cells have the ability to reshape the surrounding microenvironment for their survival, growth, invasion, and immune escape (Quail and Joyce, 2013;Spranger and Gajewski, 2018). Our study and those by others have demonstrated that PTEN loss or PI3K-AKT pathway activation promote an immunosuppressive microenvironment, resulting in silenced immune response, decreased tumor antigen presentation and decreased CD8 + T cell infiltration, which lead to resistance to ICT (Chandrasekaran et al, 2019;Garcia et al, 2014;George et al, 2017;Peng et al, 2016;Sivaram et al, 2019;Wu et al, 2019). We found in this study that PI3K inhibition by BAY1082439 not only inhibits PTEN null prostate cancer cell growth, but also promotes anti-tumor immunity via increased IFNα and IFNγ pathway activities, upregulated expression and secretion of crucial CD8 + T cell attracting cytokines and increased antigen presentation (Fig.1).…”

“…However, targeting PI3K pathway is not a simple task, especially to achieve synergy with ICT, as PI3K pathway plays significant roles on both sides of the aisle. As one of the most important oncogenic pathways, PI3K activation promotes cell proliferation, survival, migration, angiogenesis, metabolic reprograming as well as an immune suppressive environment (Cheng et al, 2020;Okkenhaug et al, 2016;Sivaram et al, 2019;Thorpe et al, 2015;Wu et al, 2019); on the other hand, PI3K is also a critical regulator for the functions of immune cells within the tumor microenvironment, and inhibition of PI3K activity in these immune cells may be detrimental for ICT (Carnevalli et al, 2018;De Henau et al, 2016;Kaneda et al, 2016;Lu et al, 2017). To make things even more complicated, there are four isoforms in the class I PI3K family:…”