title: Biphasic Rapamycin Effects in Lymphoma and Carcinoma Treatment.
abstract: mTOR drives tumor growth but also supports T-cell function, rendering the applications of mTOR inhibitors complex especially in T-cell malignancies. Here, we studied the effects of the mTOR inhibitor rapamycin in mouse EL4 T-cell lymphoma. Typical pharmacologic rapamycin (1-8 mg/kg) significantly reduced tumor burden via direct suppression of tumor cell proliferation and improved survival in EL4 challenge independent of antitumor immunity. Denileukin diftitox (DD)-mediated depletion of regulatory T cells significantly slowed EL4 growth in vivo in a T-cell-dependent fashion. However, typical rapamycin inhibited T-cell activation and tumor infiltration in vivo and failed to boost DD treatment effects. Low-dose (LD) rapamycin (75 μg/kg) increased potentially beneficial CD44hiCD62L+CD8+central memory T cells in EL4 challenge, but without clinical benefit. LD rapamycin significantly enhanced DD treatment efficacy, but DD plus LD rapamycin treatment effects were independent of antitumor immunity. Instead, rapamycin upregulated EL4 IL2 receptor in vitro and in vivo, facilitating direct DD tumor cell killing. LD rapamycin augmented DD efficacy against B16 melanoma and a human B-cell lymphoma, but not against human Jurkat T-cell lymphoma or ID8agg ovarian cancer cells. Treatment effects correlated with IL2R expression, but mechanisms in some tumors were not fully defined. Overall, our data define a distinct, biphasic mechanisms of action of mTOR inhibition at doses that are clinically exploitable, including in T-cell lymphomas. Cancer Res; 77(2); 520-31. ©2016 AACR.
authors.affiliation: The Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, Texas.|Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.|Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas.|Xiangya School of Medicine, Central South University, Changsha, Hunan, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Pandeswara
authors.affiliation: The Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, Texas.|Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Vinh
authors.initials: V
authors.lastname: Dao
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Padrón
authors.affiliation: The Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Drerup
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Shunhua
authors.initials: S
authors.lastname: Lao
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Aijie
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Vincent
authors.initials: V
authors.lastname: Hurez
authors.affiliation: The Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, Texas. curielt@uthscsa.edu.|Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.|Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004167:Diphtheria Toxin / Q000494:pharmacology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000494:pharmacology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D016399:Lymphoma, T-Cell / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D020123:Sirolimus / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D004167:Diphtheria Toxin; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox; D020123:Sirolimus