- Epidemiologic studies depict a negative correlation between caffeine consumption and incidence of tumors in humans. The main pharmacological effects of caffeine are mediated by antagonism of the adenosine receptor, A2AR. Here, weexamine whether the targeting of A2AR by caffeine plays a role in anti-tumor immunity. In particular,the effects of caffeine are studied in wild-type and A2ARknockout (A2AR(-/-)) mice. Tumor induction was achieved usingthe carcinogen 3-methylcholanthrene (3-MCA). Alternatively, tumor cells,comprised of 3-MCA-induced transformed cells or B16 melanoma cells, were inoculated into animalfootpads.Cytokine release was determined in a mixed lymphocyte tumor reaction (MLTR). According to our findings, caffeine-consumingmice (0.1% in water) developed tumorsat a lower rate compared to water-consuming mice (14% vs. 53%, respectively, p=0.0286, n=15/group). Within the caffeine-consuming mice, tumor-free mice displayed signs of autoimmune alopecia and pronounced leukocyte recruitment intocarcinogen injection sites. Similarly, A2AR(-/-) mice exhibited reduced rates of 3-MCA-induced tumors. In tumor inoculation studies, caffeine treatment resulted in inhibition of tumor growth and elevation inproinflammatorycytokine releaseover water-consuming mice, as depicted by MLTR. Addition of the adenosine receptor agonist, NECA, to MLTR resulted in a sharp decrease in IFNγlevels;this was reversed bythehighly selectiveA2AR antagonist, ZM241385. Thus,immune response modulation through either caffeine or genetic deletion of A2AR leads to a Th1 immune profile and suppression of carcinogen-inducedtumorigenesis.Taken together, our data suggestthat the use of pharmacologic A2AR antagonistsmay hold therapeutic potential in diminishing the rate of cancer development. Copyright © 2015. Published by Elsevier Inc.