Immune-Stimulatory Effects of Rapamycin Are Mediated by Stimulation of Antitumor γδ T Cells

The FDA-approved mTOR inhibitor rapamycin mediates important immune effects, but its contributions to the anticancer effects of the drug are unclear. Here we report evidence that rapamycin-mediated cancer protection relies upon stimulation of γδ T cells. In a well-established mouse model of carcinog...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2016-10, Vol.76 (20), p.5970-5982
Main Authors: Dao, Vinh, Liu, Yang, Pandeswara, Srilakshmi, Svatek, Robert S, Gelfond, Jonathan A, Liu, Aijie, Hurez, Vincent, Curiel, Tyler J
Format: Article
Language:English
Subjects:
9,10-Dimethyl-1,2-benzanthracene
Adjuvants, Immunologic - pharmacology
Animals
Cell Movement
Chemokine CXCL10 - physiology
Cytotoxicity, Immunologic - drug effects
Female
Humans
Interferon-gamma - physiology
Mice
Mice, Inbred C57BL
Receptors, Antigen, T-Cell, gamma-delta - analysis
Receptors, CXCR3 - physiology
Sirolimus - pharmacology
Skin Neoplasms - prevention & control
T-Lymphocyte Subsets - drug effects
T-Lymphocyte Subsets - immunology
TOR Serine-Threonine Kinases - antagonists & inhibitors
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Summary:The FDA-approved mTOR inhibitor rapamycin mediates important immune effects, but its contributions to the anticancer effects of the drug are unclear. Here we report evidence that rapamycin-mediated cancer protection relies upon stimulation of γδ T cells. In a well-established mouse model of carcinogen and inflammation-driven skin carcinogenesis, IFNγ recruited γδ TCR T cells to the epidermis where rapamycin boosted their perforin-dependent antitumor properties. These antitumor cells were mostly Vγ5 Vγ4 Vγ1 in phenotype. IFNγ signals were required in both hematopoietic and nonhematopoietic cells for rapamycin to optimally promote epidermal infiltration of γδ TCR T cells, as mediated by CXCR3-CXCL10 interactions, along with the antitumor effects of these cells. In mouse xenograft models of human squamous cell carcinoma, rapamycin improved human γδ T-cell-mediated cancer cell killing. Our results identify immune mechanisms for the cancer prevention and treatment properties of rapamycin, challenging the paradigm that mTOR inhibition acts primarily by direct action on tumor cells. Cancer Res; 76(20); 5970-82. ©2016 AACR.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-16-0091