Delta-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway.
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.
Zhu
L X
LX
Pulmonary Immunology Laboratory and Division of Pulmonary and Critical Care Medicine, University of California, Los Angeles, School of Medicine, 90095, USA.
Sharma
S
S
Stolina
M
M
Gardner
B
B
Roth
M D
MD
Tashkin
D P
DP
Dubinett
S M
SM
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000938:Antigen-Presenting Cells / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000502:physiology*; D013759:Dronabinol / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000008:administration & dosage; D007113:Immunity, Innate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D016753:Interleukin-10 / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000502:physiology*; D016511:Severe Combined Immunodeficiency / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D016207:Cytokines; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D013759:Dronabinol