Abstract
In this study, we show that Delta-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, suppresses host immune reactivity against lung cancer. In two different weakly immunogenic murine lung cancer models, intermittent administration of THC (5 mg/kg, four times/wk i.p. for 4 wk) led to accelerated growth of tumor implants compared with treatment with diluent alone. In contrast to our findings in immunocompetent mice, THC did not affect tumor growth in tumor-bearing SCID mice. The immune inhibitory cytokines, IL-10 and TGF-beta, were augmented, while IFN-gamma was down-regulated at both the tumor site and in the spleens of THC-treated mice. Administration of either anti-IL-10- or anti-TGF-beta-neutralizing Abs prevented the THC-induced enhancement in tumor growth. Both APC and T cells from THC-treated mice showed limited capacities to generate alloreactivity. Furthermore, lymphocytes from THC-treated mice transferred the effect to normal mice, resulting in accelerated tumor growth similar to that seen in the THC-treated mice. THC decreased tumor immunogenicity, as indicated by the limited capacity for tumor-immunized, THC-treated mice to withstand tumor rechallenge. In vivo administration of a specific antagonist of the CB2 cannabinoid receptor also blocked the effects of THC. Our findings suggest the THC promotes tumor growth by inhibiting antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adoptive Transfer
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Animals
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Antibodies, Monoclonal / administration & dosage
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Antigen-Presenting Cells / immunology
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Carcinoma, Lewis Lung / immunology*
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Carcinoma, Lewis Lung / pathology
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Carcinoma, Lewis Lung / prevention & control
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Cell Division / drug effects
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Cell Division / immunology
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Cytokines / physiology*
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Dronabinol / antagonists & inhibitors
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Dronabinol / metabolism
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Dronabinol / pharmacology*
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Growth Inhibitors / administration & dosage
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Immunity, Innate / drug effects
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Immunosuppressive Agents / antagonists & inhibitors
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Immunosuppressive Agents / metabolism
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Immunosuppressive Agents / pharmacology*
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Injections, Intraperitoneal
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Interleukin-10 / immunology
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Lymphocyte Culture Test, Mixed
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Lymphocyte Subsets / drug effects
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Lymphocyte Subsets / immunology
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Lymphocyte Subsets / metabolism
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Lymphocyte Subsets / transplantation
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Lymphocyte Transfusion
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, SCID
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Neoplasm Transplantation
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Receptors, Cannabinoid
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Receptors, Drug / physiology*
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Severe Combined Immunodeficiency / immunology
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T-Lymphocytes / immunology
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Transforming Growth Factor beta / immunology
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Tumor Cells, Cultured
Substances
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Antibodies, Monoclonal
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Cytokines
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Growth Inhibitors
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Immunosuppressive Agents
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Receptors, Cannabinoid
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Receptors, Drug
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Transforming Growth Factor beta
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Interleukin-10
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Dronabinol