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The Khleif Laboratory focusses on enhancing the anti-tumor immune response by optimizing the activation of tumor-specific cytotoxic T lymphocytes (CD8+ effector T cells) while subsiding the immune suppressive mechanisms within the tumor microenvironment, mostly through minimizing the activity of
regulatory T lymphocytes (Tregs). Previous studies demonstrated the major role of the PI3K/Akt signaling pathway and its Class IA isoforms (PI3Ka, PI3Kb, and PI3Kd) in the activation, proliferation, and survival of conventional T cells (Tconv) as well as Tregs. Moreover, PI3K/Akt inhibitors were able to enhance
the antitumor immune response that is possibly translated into their therapeutic efficacy.
Akt isoforms, and their specific roles in the proliferation and differentiation of cytotoxic T lymphocytes
(CD8+ T cells), have been the subject of an ongoing investigation in the Khleif Laboratory. It was shown
previously that Akt1 and Akt2, but not Akt3, drive the terminal differentiation step of CD8+ T cells;
hence, their inhibition may enhance the anti-tumor immune response by increasing the population of
potent central (TCM) memory cells rather than terminal CD8+ memory cells. Moreover, it has been observed that the inhibition of Akt1 and Akt2, but not Akt 3, preserves naïve and central CD8+ memory T
cells (CD8+ TCMs), delays CD8+ T-cell exhaustion, and enhances their proliferative as well as cytokine
and Granzyme B production ability and eventually prolongs their survival. Based on these investigations,
they have also defined a mechanism in which proliferative potential, function, and survival of CD8+ T
cells would be enhanced by maintaining a reservoir of TCM and naïve cells using only Akt1 and Akt2 inhibition (Oncoimmunology. 2015, 4(5):e1005448). The results of these preclinical studies clarifies the previously unanswered questions regarding the correlation between the signaling pathways and the immune response and may enhance efficacy of the combination therapeutic approach to cancers in the
clinical setting