The mechanistic target of rapamycin (mTOR) integrates environmental inputs to regulate cellular growth and metabolism in tumors. However, mTOR also regulates T-cell differentiation and activation, rendering applications of mTOR inhibitors towards treating cancer complex. Preclinical data supports distinct biphasic effects of rapamycin, with higher doses directly suppressing tumor cell growth and lower doses enhancing T-cell immunity. To address the translational relevance of these findings, the effects of the mTOR complex 1 (mTORC1) inhibitor, rapamycin, on tumor and T cells were monitored in patients undergoing cystectomy for bladder cancer (BC). MB49 syngeneic murine BC models were tested to gain mechanistic insights. Surgery induced T-cell exhaustion in humans and mice and was associated with increased pulmonary metastasis and decreased PD-L1 antibody efficacy in mouse BC. At 3 mg orally daily, rapamycin concentrations were 2-fold higher in bladder tissues than in blood. Rapamycin significantly inhibited tumor mTORC1, shown by decreased rpS6 phosphorylation in treated versus control patients (P=0.008). Rapamycin reduced surgery-induced T-cell exhaustion in patients, evidenced by a significant decrease in the prevalence of dysfunctional programmed death-1 (PD-1)-expressing T cells. Grade 3-4 adverse event rates were similar between groups, but rapamycin-treated patients had a higher rate of wound complications versus controls. In conclusion, surgery promoted BC metastasis and decreased the efficacy of post-operative BC immunotherapy. Low dose (3 mg daily) oral rapamycin has favorable pharmacodynamic and immune modulating activity in surgical patients and has potential to decrease surgery-induced immune dysfunction.
Cancer immunology research. 2018 Dec 18 [Epub ahead of print]
Robert S Svatek, Niannian Ji, Essel Marie B de Leon, Neelam Mukherjee, Aashish Kabra, Vincent Hurez, Marlo Nicolas, Joel E Michalek, Martin Javors, Karen Wheeler, Zelton Dave Sharp, Carolina B Livi, Zhen-Ju Shu, David N Henkes, Tyler J Curiel
Experimental Development Therapeutics Program/Urology, The Cancer Therapy and Research Center/UT Health Science Center ., Urology, UT Health Science Center at San Antonio., Department of Pathology, University of Texas Health Science Center at San Antonio., Urology, University of Texas Health Science Center at San Antonio., Experimental Developmental Therapeutics (EDT) Program and Urology, The Cancer Therapy and Research Center/UT Health San Antonio., Medicine/Hematology&Medical Oncology, UT Health Science Center at San Antonio., Pathology, UT Health San Antonio., Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio., Psychiatry, UT Health San Antonio., Experimental Development Therapeutics Program/Urology, The Cancer Therapy and Research Center/UT Health Science Center., Molecular Medicine, University of Texas Health Sciences Center at San Antonio., The University of Texas Health Science Center at San Antonio., Pathology, CHRISTUS Santa Rosa Medical Center., The Graduate School of Biomedical Sciences, University of Texas Health Science Center.