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-9-Tetrahydrocannabinol Inhibits Antitumor Immunity by a CB2 Receptor-Mediated, Cytokine-Dependent Pathway1
,
,
*
Pulmonary Immunology Laboratory and
Division of Pulmonary and Critical Care Medicine, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095; and
Veterans Affairs West Los Angeles Healthcare Center, Los Angeles, CA 90073
In this study, we show that 
-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-ß, were augmented, while IFN-
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-ß-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.
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