Pi3k/Akt Pathway: The Indestructible Role Of A Vintage Target As A Support To The Most Recent Immunotherapeutic Approaches

Simple Summary PI3K/Akt pathway has an impressive story as tumor marker. PI3K-dependent solid tumors have been studied for several years in order to inhibit the pathway at different levels along the signaling. Despite the highly satisfactory results obtained in vitro and in xenograft mouse tumor models, the use of PI3K/Akt inhibitors in clinical trials resulted in being not as efficient as expected. With the emerging role of the tumor microenvironment in the response to therapy and the awareness, increasing in recent years, of the necessity to army the immune system against the tumor, new opportunities have emerged for PI3K/Akt inhibitors. Here, we show that PI3K/Akt, in addition to its function as tumor marker, exerts a pivotal role as an immunomodulator. Recent studies demonstrate that PI3K/Akt pathway is crucial for the regulation of the immune system and that its inhibition in combination with immunomodulatory agents may provide a new therapeutic approach for cancer. Pathologic activation of PI3Ks and the subsequent deregulation of its downstream signaling pathway is among the most frequent events associated with cellular transformation, cancer, and metastasis. PI3Ks are also emerging as critical factors in regulating anti-tumor immunity by either promoting an immunosuppressive tumor microenvironment or by controlling the activity and the tumor infiltration of cells involved in the immune response. For these reasons, significant pharmaceutical efforts are dedicated to inhibiting the PI3K pathway, with the main goal to target the tumor and, at the same time, to enhance the anti-tumor immunity. Recent immunotherapeutic approaches involving the use of adoptive cell transfer of autologous genetically modified T cells or immune check-point inhibitors showed high efficacy. However, mechanisms of resistance to these kinds of therapy are emerging, due in part to the inhibition of effector T cell functions exerted by the immunosuppressive tumor microenvironment. Here, we first describe how inhibition of PI3K/Akt pathway contribute to enhance anti-tumor immunity and further discuss how inhibitors of the pathway are used in combination with different immunomodulatory and immunotherapeutic agents to improve anti-tumor efficacy.