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
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Research Support, U.S. Gov't, P.H.S.
MeSH terms
- Adoptive Transfer
- Animals
- Antibodies, Monoclonal / administration & dosage
- Antigen-Presenting Cells / immunology
- Carcinoma, Lewis Lung / immunology*
- Carcinoma, Lewis Lung / pathology
- Carcinoma, Lewis Lung / prevention & control
- Cell Division / drug effects
- Cell Division / immunology
- Cytokines / physiology*
- Dronabinol / antagonists & inhibitors
- Dronabinol / metabolism
- Dronabinol / pharmacology*
- Growth Inhibitors / administration & dosage
- Immunity, Innate / drug effects
- Immunosuppressive Agents / antagonists & inhibitors
- Immunosuppressive Agents / metabolism
- Immunosuppressive Agents / pharmacology*
- Injections, Intraperitoneal
- Interleukin-10 / immunology
- Lymphocyte Culture Test, Mixed
- Lymphocyte Subsets / drug effects
- Lymphocyte Subsets / immunology
- Lymphocyte Subsets / metabolism
- Lymphocyte Subsets / transplantation
- Lymphocyte Transfusion
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, SCID
- Neoplasm Transplantation
- Receptors, Cannabinoid
- Receptors, Drug / physiology*
- Severe Combined Immunodeficiency / immunology
- T-Lymphocytes / immunology
- Transforming Growth Factor beta / immunology
- Tumor Cells, Cultured
Substances
- Antibodies, Monoclonal
- Cytokines
- Growth Inhibitors
- Immunosuppressive Agents
- Receptors, Cannabinoid
- Receptors, Drug
- Transforming Growth Factor beta
- Interleukin-10
- Dronabinol