Integrated Akt/PKB signaling in immunomodulation and its potential role in cancer immunotherapy

T cell development and maturation involve a variety of defined and coordinated developmental stages under the control of a variety of signaling networks. They function as the major mediator in cell-based immunity that defends against pathogen infections and executes immune surveillance against tumor cells. Protein kinase B (PKB, also called Akt) is central to multiple signaling pathways and transduces extracellular signals to dictate cellular responses towards proliferation, migration, anti-apoptosis, and maintenance of metabolic homeostasis. Although the prosurvival function of PKB was thought to be responsible for most of the functions regulated by PKB, emerging evidence has started to dissect its role in immunomodulation. More importantly, hyperactivation of PKB in cancer stroma frequently occurs in patients treated clinically with targeted cancer therapies, where it acts as a key mediator involved in the trapping of host immune cells in the vicinity of tumors, which supports cancer cell invasion and the escape of cancer cells from host immune surveillance. Encouragingly, recent studies have shown that inhibition of PKB improves the recognition of cancer cells by the host immune system, indicating a potential clinical strategy to rekindle the suppressed host immune response through the specific targeting of PKB. In this review, we explore how PKB signaling contributes to T cell development and cellular immune responses and discuss the mechanistic roles that PKB plays in the creation of immunosuppressive conditions and the escaping of immune recognition in the microenvironment of cancer.