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Development and characterization of molecular and immunological strategies

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. Considering the possibility of a multidisciplinary approach in cancer treatment, the Khleif Laboratory has been also investigating combining both stimulating (anti-OX40, anti-GITR) and inhibitory (anti-PD-1, antiPD-L1, anti-CTLA-4) monoclonal antibodies, small molecule kinase inhibitors, and the HPV16E7 cancer vaccine in a murine lung-epithelial TC-1 tumor model to induce complete tumor regression. Combining therapeutic cancer vaccines, checkpoint inhibitor monoclonal antibodies, and immune-stimulating modalities is one of the innovative treatment options in oncology that has shown promising results in many tumors previously considered to have poor prognosis, such as malignant melanoma. Page 13 Cancer immunology, Inflammation, & Tolerance Dr. Z. Kurago investigates the functions of the mucosal defenses of the upper aerodigestive tract in health and disease, including infectious disorders and malignant neoplasia. In collaboration with Drs. D. Malamud and W. Abrams (NYU), and D. Weismann (U. Penn), studies were designed to better understand the differences in HIV transmission at mucosal portals by mapping the periluminal distribution of the HIV-binding molecule gp340 (DMBT1) and HIV targets CD4+ and CD16+ cells in normal oral, cervical, and rectal/sigmoid mucosae. While soluble gp340, present in saliva, can neutralize HIV binding to cells, cell-associated gp340 facilitates transmission. This study defined important distinctions between portals of HIV entry that help explain differences in transmission rates. (PLOS One. 2015, 10(7):e0132942).