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BACKGROUND The role of the immune system in the surveillance of the body for cancer cells is well established. Human tumor cells do not survive in mice with intact immune systems, but they propagate in athymic nude mice. Presumably, the lack of a thymus gland and consequent loss of T lymphocytes results in a seriously compromised immune system without adequate cell-mediated immunity and tumor surveillance. In patients infected with the human immunodeficiency virus (HIV), a progressive loss of cell-mediated immunity is associated with the development of malignancies and opportunistic infections. This effect may be exacerbated in patients who chronically consume alcohol. METHODS Normal and alcoholic BALB/c mice were treated with a monoclonal antibody to deplete CD4+ lymphocytes before orthotopic implantation of human lung adenocarcinoma xenografts. Tumor volume and weight were measured and compared between groups. RESULTS The authors' data show that a single treatment of anti-CD4 antibody causes almost complete depletion of CD4+ lymphocytes and permits the formation of large intrapulmonary human nonsmall lung carcinoma xenografts in 100% of treated mice. All control animals injected with heat-denatured antibody failed to produce tumors. Chronic alcohol consumption by CD4-depleted mice resulted in larger tumors, compared with mice that did not receive ethanol in their diet (P = 0.05). CONCLUSIONS Depletion of CD4+ lymphocytes allows for the orthotopic growth of human lung adenocarcinoma xenografts in BALB/c mice. Furthermore, the consumption of alcohol reduces the ability of the impaired immune system to reject tumors. Cancer 2000;88:468–79. © 2000 American Cancer Society.