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Biphasic Rapamycin Effects in Lymphoma and Carcinoma Treatment.
- Source :
-
Cancer research [Cancer Res] 2017 Jan 15; Vol. 77 (2), pp. 520-531. Date of Electronic Publication: 2016 Oct 13. - Publication Year :
- 2017
-
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 <superscript>+</superscript> CD8 <superscript>+</superscript> 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.<br />Competing Interests: The authors have no relevant financial conflicts of interest to declare.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Animals
Antineoplastic Combined Chemotherapy Protocols pharmacology
Cell Line, Tumor
Cell Proliferation drug effects
Diphtheria Toxin pharmacology
Disease Models, Animal
Flow Cytometry
Humans
Interleukin-2 pharmacology
Jurkat Cells
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Recombinant Fusion Proteins pharmacology
T-Lymphocytes drug effects
Antibiotics, Antineoplastic administration & dosage
Immunotherapy methods
Lymphocyte Activation drug effects
Lymphoma, T-Cell pathology
Sirolimus administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 77
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 27737881
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-16-1140