Honokiol-mediated Inhibition of PI3K/mTOR Pathway A Potential Strategy to Overcome Immunoresistance in Glioma, Breast, and Prostate Carcinoma Without Impacting T Cell Function

• Authors: Courtney Crane, University of California, San Francisco; Amith Panner, University of California, San Francisco; Russel O. Pieper, University of California, San Francisco; Jack Arbiser, Emory University; Andrew T. Parsa, University of California, San Francisco
• Journal Title: Journal of Immunotherapy
• Volume: Volume 32, Number 6
• Publisher: Lippincott, Williams & Wilkins | 2009-07-01, Pages 585-592
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1097/CJI.0b013e3181a8efe6
• Subjects: Health Sciences, Medicine and Surgery; Health Sciences, Oncology; Health Sciences, Immunology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; Immunology; Medicine, Research & Experimental; Research & Experimental Medicine; Honokiol; PI3 kinase; immunoresistance; NATURAL PLANT PRODUCT; CANCER VACCINES; APOPTOSIS; GROWTH; IMMUNOTHERAPY; ACTIVATION; EXPRESSION; INDUCTION; MECHANISM; MELANOMA

Abstract

Inhibition of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is an appealing method for decreasing the immunoresistance and augmenting T cell-mediated immunotherapy. A major impediment to this strategy is the impact of conventional PI3K/mTOR pathway inhibitors on T cell function. In particular, rapamycin, is a well-known immunosuppressant that can decrease the activity of the PI3K/mTOR pathway in tumor cells, but also has a profound inhibitory effect on T cells. Here we show that Honokiol, a natural dietary product isolated from an extract of seed cones from Magnolia grandiflora, can decrease PI3K/mTOR pathway-mediated immunoresistance of glioma, breast and prostate cancer cell lines, without affecting critical proinflammatory T cell functions. Specifically, we show that at doses sufficient to down-regulate levels of phospho-S6 and the negative immune regulator B7-H1 in tumor cells, Honokiol does not significantly impair T cell proliferation or proinflammatory cytokine production. In contrast to classic inhibitors, including LY294002, wortmannin, AKT inhibitor III and rapamycin, Honokiol specifically decreases the PI3K/mTOR pathway activity in tumor cells, but not in freshly stimulated T cells. Collectively, our data define a unique application for Honokiol and provide the impetus to more fully elucidate the mechanism by which T cells are resistant to the effects of this particular inhibitor. Honokiol is clinically available for human testing and may serve to augment T cell-mediated cancer immunotherapy.