Δ-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response

In the current study, we tested the central hypothesis that exposure to triangle-9-tetrahydrocannabinol (triangle(9)-THC), the major psychoactive component in marijuana, can lead to enhanced growth of tumors that express low to undetectable levels of cannabinoid receptors by specifically suppressing the antitumor immune response. We demonstrated that the human breast cancer cell lines MCF-7 and MDA-MB-231 and the mouse mammary carcinoma 4TI express low to undetectable levels of cannabinoid receptors, CB1 and CB2, and that these cells are resistant to triangle(9)-THC-induced cytotoxicity. Furthermore, exposure of mice to triangle(9)-THC led to significantly elevated 4TI tumor growth and metastasis due to inhibition of the specific antitumor immune response in vivo. The suppression of the antitumor immune response was mediated primarily through CB2 as opposed to CB1. Furthermore, exposure to triangle(9)-THC led to increased production of IL-4 and IL-10, suggesting that triangle(9)-THC exposure may specifically suppress the cell-mediated Th1 response by enhancing Th2-associated cytokines. This possibility was further supported by microarray data demonstrating the up-regulation of a number of Th2-related genes and the down-regulation of a number of Th1-related genes following exposure to triangle(9)-THC. Finally, injection of anti-IL-4 and anti-IL-10 mAbs led to a partial reversal of the triangle(9)-THC-induced suppression of the immune response to 4TI. Such findings suggest that marijuana exposure either recreationally or medicinally may increase the susceptibility to and/or incidence of breast cancer as well as other cancers that do not express cannabinoid receptors and are resistant to triangle(9)-THC-induced apoptosis.